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Thematic Review| Volume 45, ISSUE 7, P1169-1196, July 2004

Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host1

  • Weerapan Khovidhunkit
    Affiliations
    Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
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  • Min-Sun Kim
    Affiliations
    Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
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  • Riaz A. Memon
    Footnotes
    Affiliations
    Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
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  • Judy K. Shigenaga
    Affiliations
    Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
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  • Arthur H. Moser
    Affiliations
    Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
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  • Kenneth R. Feingold
    Correspondence
    To whom correspondence should be addressed.
    Affiliations
    Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
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  • Carl Grunfeld
    Correspondence
    To whom correspondence should be addressed.
    Affiliations
    Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
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  • Author Footnotes
    1 This paper is dedicated to the memory of Dr. Riaz A. Memon, deceased.
Open AccessPublished:April 21, 2004DOI:https://doi.org/10.1194/jlr.R300019-JLR200
      Infection and inflammation induce the acute-phase response (APR), leading to multiple alterations in lipid and lipoprotein metabolism. Plasma triglyceride levels increase from increased VLDL secretion as a result of adipose tissue lipolysis, increased de novo hepatic fatty acid synthesis, and suppression of fatty acid oxidation. With more severe infection, VLDL clearance decreases secondary to decreased lipoprotein lipase and apolipoprotein E in VLDL. In rodents, hypercholesterolemia occurs attributable to increased hepatic cholesterol synthesis and decreased LDL clearance, conversion of cholesterol to bile acids, and secretion of cholesterol into the bile. Marked alterations in proteins important in HDL metabolism lead to decreased reverse cholesterol transport and increased cholesterol delivery to immune cells. Oxidation of LDL and VLDL increases, whereas HDL becomes a proinflammatory molecule. Lipoproteins become enriched in ceramide, glucosylceramide, and sphingomyelin, enhancing uptake by macrophages. Thus, many of the changes in lipoproteins are proatherogenic. The molecular mechanisms underlying the decrease in many of the proteins during the APR involve coordinated decreases in several nuclear hormone receptors, including peroxisome proliferator-activated receptor, liver X receptor, farnesoid X receptor, and retinoid X receptor.
      APR-induced alterations initially protect the host from the harmful effects of bacteria, viruses, and parasites. However, if prolonged, these changes in the structure and function of lipoproteins will contribute to atherogenesis.
      The acute-phase response (APR), an early, highly complex reaction of the host, is induced by injurious stimuli including infection and inflammation, trauma, burns, ischemic necrosis, and malignant growth (
      • Gabay C.
      • Kushner I.
      Acute-phase proteins and other systemic responses to inflammation.
      ). The APR is accompanied by specific changes in the concentration of plasma proteins. Proteins that increase by at least 25% during the APR are positive acute-phase proteins [e.g., C-reactive protein (CRP), serum amyloid A (SAA), and fibrinogen], whereas proteins that decrease are negative acute-phase proteins (e.g., albumin, transferrin, and α-fetoprotein) (
      • Gabay C.
      • Kushner I.
      Acute-phase proteins and other systemic responses to inflammation.
      ). Changes in acute-phase protein concentrations are largely attributable to alterations in their rate of synthesis in the liver, although similar changes occur in extrahepatic tissues. Microarrays of mouse liver after endotoxin treatment demonstrate that ∼7% of the genes respond to endotoxin challenge (
      • Yoo J.Y.
      • Desiderio S.
      Innate and acquired immunity intersect in a global view of the acute-phase response.
      ). These changes in acute-phase proteins are often species specific with regard to the magnitude and direction of change.
      The APR induced during infection/inflammation protects the host from further injury (
      • Gabay C.
      • Kushner I.
      Acute-phase proteins and other systemic responses to inflammation.
      ). Changes in acute-phase proteins neutralize invading microorganisms, minimize the extent of tissue damage, participate in the local immune response and tissue regeneration, and replenish proteins used in the inflammatory process. These changes, if present for a prolonged period of time, can lead to detrimental consequences to the host, such as the development of systemic amyloidosis after chronic infection or inflammation.
      Changes in acute-phase protein synthesis are mediated by cytokines produced in response to a variety of stimuli in multiple cell types, including macrophages, monocytes, T-lymphocytes, and endothelial cells (
      • Gabay C.
      • Kushner I.
      Acute-phase proteins and other systemic responses to inflammation.
      ). Key cytokines responsible for the coordination of both immune and inflammatory responses include tumor necrosis factors (TNF-α and TNF-β), interleukins (ILs), and interferons (IFN-α, -β, and -γ) (
      • Gabay C.
      • Kushner I.
      Acute-phase proteins and other systemic responses to inflammation.
      ). Redundancy classically occurs in essential parts of the host response, as several structurally different cytokines may exert similar biological effects even though they bind to different receptors. Combinations of certain cytokines produce additive or synergistic effects, whereas other cytokines may have inhibitory effects, indicating the complex nature of the host response (
      • Okusawa S.
      • Gelfand J.A.
      • Ikejima T.
      • Connolly R.J.
      • Dinarello C.A.
      Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition.
      ,
      • Yokota T.
      • Arai N.
      • de Vries J.
      • Spits H.
      • Banchereau J.
      • Zlotnik A.
      • Rennick D.
      • Howard M.
      • Takebe Y.
      • Miyatake S.
      • Lee F.
      • Arai K.
      Molecular biology of interleukin 4 and interleukin 5 genes and biology of their products that stimulate B cells, T cells and hemopoietic cells.
      ,
      • de Waal Malefyt R.
      • Yssel H.
      • Roncarolo M.G.
      • Spits H.
      • de Vries J.E.
      Interleukin-10.
      ).
      Infection and inflammation are accompanied by similar cytokine-induced alterations in lipid and lipoprotein metabolism. Of note, inflammatory cytokines are increased and play a pathogenic role in a variety of very common disorders, such as diabetes, obesity, metabolic syndrome, hypertension, chronic heart failure, chronic renal failure, and atherosclerosis (
      • Pickup J.C.
      • Crook M.A.
      Is type II diabetes mellitus a disease of the innate immune system?.
      ,
      • Pradhan A.D.
      • Ridker P.M.
      Do atherosclerosis and type 2 diabetes share a common inflammatory basis?.
      ,
      • Huerta M.G.
      • Nadler J.L.
      Role of inflammatory pathways in the development and cardiovascular complications of type 2 diabetes.
      ,
      • Grimble R.F.
      Inflammatory status and insulin resistance.
      ,
      • Yudkin J.S.
      • Kumari M.
      • Humphries S.E.
      • Mohamed-Ali V.
      Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?.
      ,
      • Sharma R.
      • Al-Nasser F.O.
      • Anker S.D.
      The importance of tumor necrosis factor and lipoproteins in the pathogenesis of chronic heart failure.
      ,
      • Young J.L.
      • Libby P.
      • Schonbeck U.
      Cytokines in the pathogenesis of atherosclerosis.
      ). Many of these disorders display abnormalities in lipid metabolism that are similar to those that occur during infection and inflammation.
      This review summarizes the changes in lipid and lipoprotein during infection/inflammation and their molecular mechanisms. Most mechanistic studies were carried out in animal models of infection using endotoxin [lipopolysaccharide (LPS)], a well-characterized inducer of cytokines and the APR, or the proinflammatory cytokines (TNF and IL-1), which mediate the APR. We describe the role of transcription factors in regulating lipid metabolism during infection/inflammation. Finally, we discuss both the beneficial effects and deleterious consequences to the host of APR-induced changes in lipid and lipoprotein metabolism.

      CHANGES IN LIPID AND LIPOPROTEIN METABOLISM DURING INFECTION AND INFLAMMATION

      An early and consistent metabolic alteration during infection/inflammation is increased serum triglyceride (TG) levels, characterized by an increase in VLDL levels (
      • Hardardóttir I.
      • Grunfeld C.
      • Feingold K.R.
      Effects of endotoxin on lipid metabolism.
      ). Multiple mechanisms produce hypertriglyceridemia during the APR; several cytokines are capable of producing these changes. Whether an increase in glucocorticoid levels during infection plays a role in lipid metabolism is unclear.
      The effects of infection and inflammation on TG metabolism are similar in all species, whereas changes in cholesterol metabolism differ between rodents and primates. In rodents, there is an increase in serum total cholesterol levels and hepatic cholesterol synthesis, whereas nonhuman primates and humans have either no change or a decrease in serum cholesterol and LDL levels (
      • Hardardóttir I.
      • Grunfeld C.
      • Feingold K.R.
      Effects of endotoxin on lipid metabolism.
      ). The mechanisms underlying this species difference is not known. HDL levels are decreased in both rodents and primates during the APR, and there are marked changes in proteins associated with HDL metabolism (
      • Khovidhunkit W.
      • Memon R.A.
      • Feingold K.R.
      • Grunfeld C.
      Infection and inflammation-induced proatherogenic changes of lipoproteins.
      ). Finally, infection produces alterations in the composition and function of lipoproteins, including changes in sphingolipid concentrations, decreased reverse cholesterol transport (RCT), and increased oxidation of lipids.

      TG metabolism

      Patients with gram-negative or gram-positive bacterial infections and viral infections have increased serum TG levels (
      • Gallin J.I.
      • Kaye D.
      • O'Leary W.M.
      Serum lipids in infection.
      ,
      • Sammalkorpi K.
      • Valtonen V.
      • Kerttula Y.
      • Nikkila E.
      • Taskinen M.R.
      Changes in serum lipoprotein pattern induced by acute infections.
      ,
      • Grunfeld C.
      • Pang M.
      • Doerrler W.
      • Shigenaga J.K.
      • Jensen P.
      • Feingold K.R.
      Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.
      ). In animals, administration of LPS, a major component of the cell wall of gram-negative bacteria, or lipoteichoic acid (LTA), a component of the cell wall of gram-positive bacteria, produces hypertriglyceridemia (
      • Fiser R.H.
      • Shultz T.D.
      • Rindsig R.B.
      • Beisel W.R.
      Alterations in plasma and brain lipid metabolism during endotoxemia in the neonatal rat.
      ,
      • Kaufmann R.L.
      • Matson C.F.
      • Beisel W.R.
      Hypertriglyceridemia produced by endotoxin: role of impaired triglyceride disposal mechanisms.
      ,
      • Sakaguchi O.
      • Sakaguchi S.
      Alterations of lipid metabolism in mice injected with endotoxin.
      ,
      • Scholl R.A.
      • Lang C.H.
      • Bagby G.J.
      Hypertriglyceridemia and its relation to tissue lipoprotein lipase activity in endotoxemic, Escherichia coli bacteremic, and polymicrobial septic rats.
      ,
      • Gaal D.
      • Kremmer T.
      • Balint Z.
      • Holczinger L.
      • Bertok L.
      • Nowotny A.
      Effects of bacterial endotoxins and their detoxified derivatives on serum and liver lipids in mice.
      ,
      • Kawakami M.
      • Murase T.
      • Itakura H.
      • Yamada N.
      • Ohsawa N.
      • Takaku F.
      Lipid metabolism in endotoxic rats: decrease in hepatic triglyceride lipase activity.
      ,
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Ettinger W.H.
      • Miller L.D.
      • Albers J.J.
      • Smith T.K.
      • Parks J.S.
      Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin:cholesterol acyltransferase in cynomolgus monkeys.
      ,
      • Feingold K.R.
      • Staprans I.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Doerrler W.
      • Dinarello C.A.
      • Grunfeld C.
      Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
      ,
      • Feingold K.R.
      • Hardardottir I.
      • Memon R.
      • Krul E.J.
      • Moser A.H.
      • Taylor J.M.
      • Grunfeld C.
      Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
      ,
      • Nonogaki K.
      • Moser A.H.
      • Pan X.M.
      • Staprans I.
      • Grunfeld C.
      • Feingold K.R.
      Lipoteichoic acid stimulates lipolysis and hepatic triglyceride secretion in rats in vivo.
      ) (Table 1). Multiple cytokines increase serum TG levels in rodents and in humans (
      • Feingold K.R.
      • Grunfeld C.
      Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo.
      ,
      • Argiles J.M.
      • Lopez-Soriano F.J.
      • Evans R.D.
      • Williamson D.H.
      Interleukin-1 and lipid metabolism in the rat.
      ,
      • Feingold K.R.
      • Soued M.
      • Serio M.K.
      • Moser A.H.
      • Dinarello C.A.
      • Grunfeld C.
      Multiple cytokines stimulate hepatic lipid synthesis in vivo.
      ,
      • Feingold K.R.
      • Soued M.
      • Adi S.
      • Staprans I.
      • Neese R.
      • Shigenaga J.
      • Doerrler W.
      • Moser A.
      • Dinarello C.A.
      • Grunfeld C.
      Effect of interleukin-1 on lipid metabolism in the rat. Similarities to and differences from tumor necrosis factor.
      ,
      • Memon R.A.
      • Grunfeld C.
      • Moser A.H.
      • Feingold K.R.
      Tumor necrosis factor mediates the effects of endotoxin on cholesterol and triglyceride metabolism in mice.
      ,
      • Nonogaki K.
      • Fuller G.M.
      • Fuentes N.L.
      • Moser A.H.
      • Staprans I.
      • Grunfeld C.
      • Feingold K.R.
      Interleukin-6 stimulates hepatic triglyceride secretion in rats.
      ,
      • Sherman M.L.
      • Spriggs D.R.
      • Arthur K.A.
      • Imamura K.
      • Frei 3rd, E.
      • Kufe D.W.
      Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.
      ,
      • Malmendier C.L.
      • Lontie J.F.
      • Sculier J.P.
      • Dubois D.Y.
      Modifications of plasma lipids, lipoproteins and apolipoproteins in advanced cancer patients treated with recombinant interleukin-2 and autologous lymphokine-activated killer cells.
      ,
      • Starnes Jr., H.F.
      • Warren R.S.
      • Jeevanandam M.
      • Gabrilove J.L.
      • Larchian W.
      • Oettgen H.F.
      • Brennan M.F.
      Tumor necrosis factor and the acute metabolic response to tissue injury in man.
      ,
      • Kurzrock R.
      • Rohde M.F.
      • Quesada J.R.
      • Gianturco S.H.
      • Bradley W.A.
      • Sherwin S.A.
      • Gutterman J.U.
      Recombinant gamma interferon induces hypertriglyceridemia and inhibits post-heparin lipase activity in cancer patients.
      ,
      • Olsen E.A.
      • Lichtenstein G.R.
      • Wilkinson W.E.
      Changes in serum lipids in patients with condylomata acuminata treated with interferon alfa-n1 (Wellferon).
      ,
      • Naeem M.
      • Bacon B.R.
      • Mistry B.
      • Britton R.S.
      • Di Bisceglie A.M.
      Changes in serum lipoprotein profile during interferon therapy in chronic hepatitis C.
      ). The hypertriglyceridemic effect of LPS and cytokines is rapid, occurring within 2 h after administration, and is sustained for at least 24 h (
      • Feingold K.R.
      • Staprans I.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Doerrler W.
      • Dinarello C.A.
      • Grunfeld C.
      Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
      ,
      • Feingold K.R.
      • Grunfeld C.
      Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo.
      ). The doses of LPS or cytokines that produce hypertriglyceridemia in rodents are similar to those that produce fever, anorexia, and changes in acute-phase protein synthesis, suggesting that hypertriglyceridemia is a very sensitive, physiological part of the host response to infection rather than a manifestation of toxicity (
      • Feingold K.R.
      • Staprans I.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Doerrler W.
      • Dinarello C.A.
      • Grunfeld C.
      Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
      ).
      TABLE 1Effects of LPS, LTA, and cytokines on TG metabolism in intact animals
      VariableLPSLTATNFIL-1IL-6IFN-αIFN-γ
      Serum TG
      Hepatic FA synthesis
      TG secretionNDND
      Lipolysis
      FA oxidationNDNDNDND
      Serum ketone bodyND
      Low doses.
      , ↔
      High doses.
      TG clearance
      Low doses.
      , ↓
      High doses.
      NDND
      LPL activity↓, ↔
      Some but not most tissues.
      IL, interleukin; LPL, lipoprotein lipase; LPS, lipopolysaccharide; LTA, lipoteichoic acid; ND, not determined; TG, triglyceride; TNF, tumor necrosis factor.
      a Low doses.
      b High doses.
      c Some but not most tissues.
      The increased VLDL is secondary to either increased VLDL production or decreased VLDL clearance, depending upon the dose of LPS (
      • Feingold K.R.
      • Staprans I.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Doerrler W.
      • Dinarello C.A.
      • Grunfeld C.
      Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
      ). At low doses, VLDL production increases as a result of increased hepatic FA synthesis, activation of adipose tissue lipolysis, and suppression of FA oxidation and ketogenesis. All of these mechanisms provide more FA substrate in the liver for esterification into TG and secretion as VLDL. At higher doses of LPS, VLDL clearance is decreased as a result of decreases in the activity of lipoprotein lipase (LPL), the enzyme responsible for the catabolism of TG-rich lipoproteins, and decrease in levels of apolipoprotein E (apoE).
      Serum TG levels are increased by multiple cytokines, including TNF, IL-1, IL-2, IL-6, leukemia inhibitory factor (LIF), ciliary neurotropic factor (CNTF), nerve growth factor (NGF), keratinocyte growth factor (KGF), platelet-activating factor (PAF), and parathyroid hormone-related protein (PTHrP) (
      • Argiles J.M.
      • Lopez-Soriano F.J.
      • Evans R.D.
      • Williamson D.H.
      Interleukin-1 and lipid metabolism in the rat.
      ,
      • Feingold K.R.
      • Soued M.
      • Adi S.
      • Staprans I.
      • Neese R.
      • Shigenaga J.
      • Doerrler W.
      • Moser A.
      • Dinarello C.A.
      • Grunfeld C.
      Effect of interleukin-1 on lipid metabolism in the rat. Similarities to and differences from tumor necrosis factor.
      ,
      • Memon R.A.
      • Grunfeld C.
      • Moser A.H.
      • Feingold K.R.
      Tumor necrosis factor mediates the effects of endotoxin on cholesterol and triglyceride metabolism in mice.
      ,
      • Nonogaki K.
      • Fuller G.M.
      • Fuentes N.L.
      • Moser A.H.
      • Staprans I.
      • Grunfeld C.
      • Feingold K.R.
      Interleukin-6 stimulates hepatic triglyceride secretion in rats.
      ,
      • Sherman M.L.
      • Spriggs D.R.
      • Arthur K.A.
      • Imamura K.
      • Frei 3rd, E.
      • Kufe D.W.
      Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.
      ,
      • Malmendier C.L.
      • Lontie J.F.
      • Sculier J.P.
      • Dubois D.Y.
      Modifications of plasma lipids, lipoproteins and apolipoproteins in advanced cancer patients treated with recombinant interleukin-2 and autologous lymphokine-activated killer cells.
      ,
      • Starnes Jr., H.F.
      • Warren R.S.
      • Jeevanandam M.
      • Gabrilove J.L.
      • Larchian W.
      • Oettgen H.F.
      • Brennan M.F.
      Tumor necrosis factor and the acute metabolic response to tissue injury in man.
      ,
      • Kurzrock R.
      • Rohde M.F.
      • Quesada J.R.
      • Gianturco S.H.
      • Bradley W.A.
      • Sherwin S.A.
      • Gutterman J.U.
      Recombinant gamma interferon induces hypertriglyceridemia and inhibits post-heparin lipase activity in cancer patients.
      ,
      • Olsen E.A.
      • Lichtenstein G.R.
      • Wilkinson W.E.
      Changes in serum lipids in patients with condylomata acuminata treated with interferon alfa-n1 (Wellferon).
      ,
      • Chajek-Shaul T.
      • Friedman G.
      • Stein O.
      • Shiloni E.
      • Etienne J.
      • Stein Y.
      Mechanism of the hypertriglyceridemia induced by tumor necrosis factor administration to rats.
      ,
      • Rosenzweig I.B.
      • Wiebe D.A.
      • Hank J.A.
      • Albers J.J.
      • Adolphson J.L.
      • Borden E.
      • Shrago E.S.
      • Sondel P.M.
      Effects of interleukin-2 (IL-2) on human plasma lipid, lipoprotein, and C-reactive protein.
      ,
      • Nonogaki K.
      • Pan X.M.
      • Moser A.H.
      • Shigenaga J.
      • Staprans I.
      • Sakamoto N.
      • Grunfeld C.
      • Feingold K.R.
      LIF and CNTF, which share the gp130 transduction system, stimulate hepatic lipid metabolism in rats.
      ,
      • Nonogaki K.
      • Moser A.H.
      • Shigenaga J.
      • Feingold K.R.
      • Grunfeld C.
      Beta-nerve growth factor as a mediator of the acute phase response in vivo.
      ,
      • Nonogaki K.
      • Pan X.M.
      • Moser A.H.
      • Staprans I.
      • Feingold K.R.
      • Grunfeld C.
      Keratinocyte growth factor increases fatty acid mobilization and hepatic triglyceride secretion in rats.
      ,
      • Evans R.D.
      • Ilic V.
      • Williamson D.H.
      Effects of platelet-activating factor on lipid metabolism in rats in vivo. Origin of the hypertriglyceridaemia.
      ,
      • Funk J.L.
      • Moser A.H.
      • Grunfeld C.
      • Feingold K.R.
      Parathyroid hormone-related protein is induced in the adult liver during endotoxemia and stimulates the hepatic acute phase response.
      ) (Table 1), suggesting redundancy. IL-4, an anti-inflammatory cytokine, opposes the action of some, but not all, of these cytokines (
      • Grunfeld C.
      • Soued M.
      • Adi S.
      • Moser A.H.
      • Fiers W.
      • Dinarello C.A.
      • Feingold K.R.
      Interleukin 4 inhibits stimulation of hepatic lipogenesis by tumor necrosis factor, interleukin 1, and interleukin 6 but not by interferon-alpha.
      ). The effects of cytokines on TG metabolism are likely direct and not mediated by hormones such as insulin, cortisol, or catecholamines, as TNF increases serum TG levels in insulinopenic diabetic animals and adrenalectomized rats (
      • Feingold K.R.
      • Soued M.
      • Staprans I.
      • Gavin L.A.
      • Donahue M.E.
      • Huang B.J.
      • Moser A.H.
      • Gulli R.
      • Grunfeld C.
      Effect of tumor necrosis factor (TNF) on lipid metabolism in the diabetic rat. Evidence that inhibition of adipose tissue lipoprotein lipase activity is not required for TNF-induced hyperlipidemia.
      ,
      • Evans R.D.
      • Williamson D.H.
      Comparison of effects of platelet-activating factor and tumour necrosis factor-alpha on lipid metabolism in adrenalectomized rats in vivo.
      ). Moreover, TNF also increases serum TG levels under various dietary conditions from high sucrose, which stimulates endogenous FA synthesis, to high fat, which suppresses endogenous FA synthesis (
      • Feingold K.R.
      • Soued M.
      • Serio M.K.
      • Adi S.
      • Moser A.H.
      • Grunfeld C.
      The effect of diet on tumor necrosis factor stimulation of hepatic lipogenesis.
      ,
      • Feingold K.R.
      • Adi S.
      • Staprans I.
      • Moser A.H.
      • Neese R.
      • Verdier J.A.
      • Doerrler W.
      • Grunfeld C.
      Diet affects the mechanisms by which TNF stimulates hepatic triglyceride production.
      ).

      Increased VLDL production

      Increased de novo FA and TG synthesis

      LPS and several cytokines, including TNF-α, TNF-β (lymphotoxin), IL-1, IL-6, IFN-α, LIF, CNTF, NGF, PAF, and PTHrP, rapidly induce de novo FA synthesis and hepatic TG synthesis in rodents (
      • Feingold K.R.
      • Staprans I.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Doerrler W.
      • Dinarello C.A.
      • Grunfeld C.
      Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
      ,
      • Feingold K.R.
      • Grunfeld C.
      Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo.
      ,
      • Feingold K.R.
      • Soued M.
      • Serio M.K.
      • Moser A.H.
      • Dinarello C.A.
      • Grunfeld C.
      Multiple cytokines stimulate hepatic lipid synthesis in vivo.
      ,
      • Feingold K.R.
      • Soued M.
      • Adi S.
      • Staprans I.
      • Neese R.
      • Shigenaga J.
      • Doerrler W.
      • Moser A.
      • Dinarello C.A.
      • Grunfeld C.
      Effect of interleukin-1 on lipid metabolism in the rat. Similarities to and differences from tumor necrosis factor.
      ,
      • Nonogaki K.
      • Fuller G.M.
      • Fuentes N.L.
      • Moser A.H.
      • Staprans I.
      • Grunfeld C.
      • Feingold K.R.
      Interleukin-6 stimulates hepatic triglyceride secretion in rats.
      ,
      • Nonogaki K.
      • Pan X.M.
      • Moser A.H.
      • Shigenaga J.
      • Staprans I.
      • Sakamoto N.
      • Grunfeld C.
      • Feingold K.R.
      LIF and CNTF, which share the gp130 transduction system, stimulate hepatic lipid metabolism in rats.
      ,
      • Nonogaki K.
      • Moser A.H.
      • Shigenaga J.
      • Feingold K.R.
      • Grunfeld C.
      Beta-nerve growth factor as a mediator of the acute phase response in vivo.
      ,
      • Funk J.L.
      • Moser A.H.
      • Grunfeld C.
      • Feingold K.R.
      Parathyroid hormone-related protein is induced in the adult liver during endotoxemia and stimulates the hepatic acute phase response.
      ,
      • Evans R.D.
      • Williamson D.H.
      Comparison of effects of platelet-activating factor and tumour necrosis factor-alpha on lipid metabolism in adrenalectomized rats in vivo.
      ,
      • Grunfeld C.
      • Soued M.
      • Adi S.
      • Moser A.H.
      • Dinarello C.A.
      • Feingold K.R.
      Evidence for two classes of cytokines that stimulate hepatic lipogenesis: relationships among tumor necrosis factor, interleukin-1 and interferon-alpha.
      ) (Table 1). Hepatic secretion of apoB also increases (
      • Tripp R.J.
      • Tabares A.
      • Wang H.
      • Lanza-Jacoby S.
      Altered hepatic production of apolipoproteins B and E in the fasted septic rat: factors in the development of hypertriglyceridemia.
      ), resulting in an increased number of VLDL particles secreted. In contrast, other cytokines, such as IL-2, IL-4, and IFN-γ, do not stimulate hepatic FA synthesis (
      • Feingold K.R.
      • Soued M.
      • Serio M.K.
      • Moser A.H.
      • Dinarello C.A.
      • Grunfeld C.
      Multiple cytokines stimulate hepatic lipid synthesis in vivo.
      ,
      • Grunfeld C.
      • Soued M.
      • Adi S.
      • Moser A.H.
      • Fiers W.
      • Dinarello C.A.
      • Feingold K.R.
      Interleukin 4 inhibits stimulation of hepatic lipogenesis by tumor necrosis factor, interleukin 1, and interleukin 6 but not by interferon-alpha.
      ).
      TNF rapidly increases hepatic FA synthesis within 1 h after administration, which is sustained for at least 17 h (
      • Feingold K.R.
      • Grunfeld C.
      Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo.
      ). The time course for stimulation of hepatic FA synthesis and VLDL secretion is consistent with the time course for TNF-induced hypertriglyceridemia (
      • Feingold K.R.
      • Grunfeld C.
      Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo.
      ,
      • Feingold K.R.
      • Serio M.K.
      • Adi S.
      • Moser A.H.
      • Grunfeld C.
      Tumor necrosis factor stimulates hepatic lipid synthesis and secretion.
      ). However, TNF does not acutely increase the total activity of the rate-limiting enzymes of FA synthesis [i.e., acetyl CoA carboxylase (ACC) and FA synthase (FAS)] or alter the phosphorylation state of ACC, a mechanism that regulates ACC activity (
      • Grunfeld C.
      • Verdier J.A.
      • Neese R.
      • Moser A.H.
      • Feingold K.R.
      Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo.
      ). Instead, TNF acutely increases intracellular concentrations of citrate, an allosteric activator of ACC (
      • Grunfeld C.
      • Verdier J.A.
      • Neese R.
      • Moser A.H.
      • Feingold K.R.
      Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo.
      ) (Fig. 1). IL-1 and IL-6 increase hepatic FA synthesis by increasing hepatic citrate levels, whereas IFN-α, which also increases hepatic FA synthesis, has no effect on citrate levels, suggesting a different mechanism (
      • Grunfeld C.
      • Soued M.
      • Adi S.
      • Moser A.H.
      • Dinarello C.A.
      • Feingold K.R.
      Evidence for two classes of cytokines that stimulate hepatic lipogenesis: relationships among tumor necrosis factor, interleukin-1 and interferon-alpha.
      ). The stimulatory effects of TNF or IL-1 and IFN-α on hepatic FA synthesis are additive or synergistic, whereas there is no such synergy between TNF and IL-1 or TNF and IL-6 (
      • Grunfeld C.
      • Soued M.
      • Adi S.
      • Moser A.H.
      • Dinarello C.A.
      • Feingold K.R.
      Evidence for two classes of cytokines that stimulate hepatic lipogenesis: relationships among tumor necrosis factor, interleukin-1 and interferon-alpha.
      ). Finally, IL-4, an anti-inflammatory cytokine, inhibits the stimulatory effects of TNF, IL-1, and IL-6 on hepatic FA synthesis by blocking the increase in hepatic citrate levels (
      • Grunfeld C.
      • Soued M.
      • Adi S.
      • Moser A.H.
      • Fiers W.
      • Dinarello C.A.
      • Feingold K.R.
      Interleukin 4 inhibits stimulation of hepatic lipogenesis by tumor necrosis factor, interleukin 1, and interleukin 6 but not by interferon-alpha.
      ). In contrast, IL-4 does not block the stimulatory effect of IFN-α on FA synthesis in liver (
      • Grunfeld C.
      • Soued M.
      • Adi S.
      • Moser A.H.
      • Fiers W.
      • Dinarello C.A.
      • Feingold K.R.
      Interleukin 4 inhibits stimulation of hepatic lipogenesis by tumor necrosis factor, interleukin 1, and interleukin 6 but not by interferon-alpha.
      ). Thus, analogous to cytokine regulation of the immune response, there are complex interactions among the metabolic effects of cytokines that may be additive, synergistic, or antagonistic.
      Figure thumbnail gr1
      Fig. 1Changes in hepatic FA metabolism during the acute-phase response (APR). Lipopolysaccharide (LPS) and cytokines increase CD36/fatty acid translocase (FAT) while decreasing fatty acid-transport protein (FATP) in the liver. CD36/FAT may transport long chain FA (LCFA) to cytosol for reesterification, which is enhanced during infection and inflammation, whereas FATP may transport FA toward mitochondria for oxidation, which is suppressed during infection. Cytokines, such as tumor necrosis factor and interleukin-1, increase hepatic FA synthesis by increasing hepatic citrate levels. Modest increases in acetyl CoA carboxylase (ACC) and FA synthase (FAS) are also observed. The expression of carnitine palmitoyl transferase-I (CPT-I) and CPT-II is decreased during sepsis. In addition, LPS and cytokines increase the levels of hepatic malonyl CoA, which further inhibits CPT-I, the rate-limiting enzyme in FA oxidation, resulting in decreased FA oxidation and suppressed ketone body (KB) production in the liver. ACS, acyl-CoA synthetase; CYT, cytosol; IMM, inner mitochondrial membrane; MM, mitochondrial matrix; OMM, outer mitochondrial membrane; PM, plasma membrane; TG, triglyceride.
      The late effects of TNF on hepatic FA synthesis are accompanied by modest increases in hepatic ACC and FAS activities (
      • Grunfeld C.
      • Verdier J.A.
      • Neese R.
      • Moser A.H.
      • Feingold K.R.
      Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo.
      ). Late increases in ACC activity in rat liver occur in a sepsis model induced by cecal ligation and puncture (
      • Kiuchi S.
      • Matsuo N.
      • Takeyama N.
      • Tanaka T.
      Accelerated hepatic lipid synthesis in fasted septic rats.
      ). Whether gene expression of ACC and/or FAS increases in the liver is currently not known.

      Increased adipose tissue lipolysis

      Adipose tissue lipolysis also provides FAs for increased hepatic TG synthesis during infection. The mobilized FAs are delivered to the liver and, instead of being oxidized, become reesterified into TGs and secreted into the circulation as VLDL.
      LPS, LTA, and several cytokines induce adipose tissue lipolysis in both intact animals and 3T3-L1 adipocytes (
      • Feingold K.R.
      • Staprans I.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Doerrler W.
      • Dinarello C.A.
      • Grunfeld C.
      Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
      ,
      • Nonogaki K.
      • Moser A.H.
      • Pan X.M.
      • Staprans I.
      • Grunfeld C.
      • Feingold K.R.
      Lipoteichoic acid stimulates lipolysis and hepatic triglyceride secretion in rats in vivo.
      ,
      • Nonogaki K.
      • Fuller G.M.
      • Fuentes N.L.
      • Moser A.H.
      • Staprans I.
      • Grunfeld C.
      • Feingold K.R.
      Interleukin-6 stimulates hepatic triglyceride secretion in rats.
      ,
      • Starnes Jr., H.F.
      • Warren R.S.
      • Jeevanandam M.
      • Gabrilove J.L.
      • Larchian W.
      • Oettgen H.F.
      • Brennan M.F.
      Tumor necrosis factor and the acute metabolic response to tissue injury in man.
      ,
      • Nonogaki K.
      • Pan X.M.
      • Moser A.H.
      • Shigenaga J.
      • Staprans I.
      • Sakamoto N.
      • Grunfeld C.
      • Feingold K.R.
      LIF and CNTF, which share the gp130 transduction system, stimulate hepatic lipid metabolism in rats.
      ,
      • Nonogaki K.
      • Pan X.M.
      • Moser A.H.
      • Staprans I.
      • Feingold K.R.
      • Grunfeld C.
      Keratinocyte growth factor increases fatty acid mobilization and hepatic triglyceride secretion in rats.
      ,
      • Feingold K.R.
      • Adi S.
      • Staprans I.
      • Moser A.H.
      • Neese R.
      • Verdier J.A.
      • Doerrler W.
      • Grunfeld C.
      Diet affects the mechanisms by which TNF stimulates hepatic triglyceride production.
      ,
      • Hikawyj-Yevich I.
      • Spitzer J.A.
      Endotoxin influence on lipolysis in isolated human and primate adipocytes.
      ,
      • Spitzer J.J.
      Lipid metabolism in endotoxic shock.
      ,
      • Green A.
      • Dobias S.B.
      • Walters D.J.
      • Brasier A.R.
      Tumor necrosis factor increases the rate of lipolysis in primary cultures of adipocytes without altering levels of hormone-sensitive lipase.
      ,
      • Kawakami M.
      • Murase T.
      • Ogawa H.
      • Ishibashi S.
      • Mori N.
      • Takaku F.
      • Shibata S.
      Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells.
      ,
      • Hauner H.
      • Petruschke T.
      • Russ M.
      • Rohrig K.
      • Eckel J.
      Effects of tumour necrosis factor alpha (TNF alpha) on glucose transport and lipid metabolism of newly-differentiated human fat cells in cell culture.
      ,
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Grunfeld C.
      In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.
      ). The effects of different cytokines are specific and dependent upon the nutritional status of the host (Table 1). TNF acutely induces lipolysis in chow-fed but not in sucrose-fed animals (
      • Feingold K.R.
      • Adi S.
      • Staprans I.
      • Moser A.H.
      • Neese R.
      • Verdier J.A.
      • Doerrler W.
      • Grunfeld C.
      Diet affects the mechanisms by which TNF stimulates hepatic triglyceride production.
      ). IL-1 does not stimulate lipolysis; its effect on serum TG levels is attributable to enhanced hepatic FA synthesis and TG secretion (
      • Feingold K.R.
      • Soued M.
      • Adi S.
      • Staprans I.
      • Neese R.
      • Shigenaga J.
      • Doerrler W.
      • Moser A.
      • Dinarello C.A.
      • Grunfeld C.
      Effect of interleukin-1 on lipid metabolism in the rat. Similarities to and differences from tumor necrosis factor.
      ). IL-6, LIF, and CNTF, which act through the same receptor transducer (gp130), stimulate both hepatic FA synthesis and adipose tissue lipolysis (
      • Nonogaki K.
      • Fuller G.M.
      • Fuentes N.L.
      • Moser A.H.
      • Staprans I.
      • Grunfeld C.
      • Feingold K.R.
      Interleukin-6 stimulates hepatic triglyceride secretion in rats.
      ,
      • Nonogaki K.
      • Pan X.M.
      • Moser A.H.
      • Shigenaga J.
      • Staprans I.
      • Sakamoto N.
      • Grunfeld C.
      • Feingold K.R.
      LIF and CNTF, which share the gp130 transduction system, stimulate hepatic lipid metabolism in rats.
      ). On the other hand, KGF stimulates lipolysis but has no effect on hepatic FA synthesis (
      • Nonogaki K.
      • Pan X.M.
      • Moser A.H.
      • Staprans I.
      • Feingold K.R.
      • Grunfeld C.
      Keratinocyte growth factor increases fatty acid mobilization and hepatic triglyceride secretion in rats.
      ). Finally, both IFN-α and IFN-γ stimulate lipolysis, but those peripherally derived FAs do not contribute to increased TG synthesis in the liver because they are oxidized, producing ketone bodies (KBs) (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Grunfeld C.
      In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.
      ).
      Lipolysis in adipose tissue is primarily driven by hormone-sensitive lipase (HSL), which is regulated either by alteration in its phosphorylation state or by induction of gene expression. Several cytokines that induce lipolysis, including TNF, IFN-α, and IFN-γ, produce a marked decrease in HSL mRNA (
      • Doerrler W.
      • Feingold K.R.
      • Grunfeld C.
      Cytokines induce catabolic effects in cultured adipocytes by multiple mechanisms.
      ), indicating that gene regulation of HSL does not play a role in cytokine-induced lipolysis. Rather, lipolysis is likely attributable to phosphorylation of HSL or its associated proteins. TNF-induced lipolysis in cultured human adipocytes is associated with the activation of mitogen-activated protein kinase kinase (MEK)-extracellular signal-related kinase (ERK) (
      • Zhang H.H.
      • Halbleib M.
      • Ahmad F.
      • Manganiello V.C.
      • Greenberg A.S.
      Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP.
      ), leading to decreases in cyclic nucleotide phosphodiesterase 3B, an enzyme that hydrolyzes cAMP. Increased intracellular cAMP consequently activates cAMP-dependent protein kinase A (PKA), which phosphorylates perilipins, phosphoproteins located at the surface of lipid droplets in adipocytes. Phosphorylation of perilipin A or B modifies lipid surfaces, allowing access of lipases to the lipid droplets, promoting lipolysis. Activation of the MEK-ERK pathway and PKA has also been shown to phosphorylate HSL and increase its lipolytic activity (
      • Zhang H.H.
      • Halbleib M.
      • Ahmad F.
      • Manganiello V.C.
      • Greenberg A.S.
      Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP.
      ,
      • Greenberg A.S.
      • Shen W.J.
      • Muliro K.
      • Patel S.
      • Souza S.C.
      • Roth R.A.
      • Kraemer F.B.
      Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway.
      ).
      LPS and cytokines may also induce lipolysis by decreasing the expression of acyl-CoA synthetase (ACS) in adipose tissue (
      • Doerrler W.
      • Feingold K.R.
      • Grunfeld C.
      Cytokines induce catabolic effects in cultured adipocytes by multiple mechanisms.
      ). ACS catalyzes the activation of long-chain FAs to acyl-CoA esters that are subsequently metabolized in anabolic or catabolic pathways depending on the type of tissue, the nutritional status, and the hormonal milieu of the host. Although FA transport across biological membranes is a bidirectional process, activation of FAs to acyl-CoA esters prevents the efflux of FAs from cells and hence renders FA transport unidirectional. In adipose tissue, ACS is primarily associated with microsomes to support the synthesis of TG for storage of energy. During the APR, there is a coordinated decrease in the mRNA expression of fatty acid transport proteins (FATPs) and ACS mRNA and activity in adipose tissue (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Fuller J.
      • Grunfeld C.
      Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines.
      ,
      • Memon R.A.
      • Fuller J.
      • Moser A.H.
      • Smith P.J.
      • Feingold K.R.
      • Grunfeld C.
      In vivo regulation of acyl-CoA synthetase mRNA and activity by endotoxin and cytokines.
      ) that likely prevents the activation and storage of FAs and may promote the mobilization of FAs.

      Decreased hepatic FA oxidation and ketogenesis

      Bacterial infections are accompanied by the suppression of hepatic FA oxidation (
      • Beylot M.
      • Guiraud M.
      • Grau G.
      • Bouletreau P.
      Regulation of ketone body flux in septic patients.
      ,
      • Takeyama N.
      • Itoh Y.
      • Kitazawa Y.
      • Tanaka T.
      Altered hepatic mitochondrial fatty acid oxidation and ketogenesis in endotoxic rats.
      ). Increased FA substrate provided by increased hepatic FA synthesis and adipose tissue lipolysis is then directed away from oxidation and channeled toward reesterification. This concept is supported by the demonstration that LPS, TNF, and IL-1 decrease mitochondrial but increase microsomal ACS activity in the liver (
      • Memon R.A.
      • Fuller J.
      • Moser A.H.
      • Smith P.J.
      • Feingold K.R.
      • Grunfeld C.
      In vivo regulation of acyl-CoA synthetase mRNA and activity by endotoxin and cytokines.
      ). Decreased mitochondrial ACS prevents the activation of FA for entry into mitochondria for oxidation, whereas increased microsomal ACS enhances the reesterification of FAs for TG synthesis.
      LPS and cytokines differentially regulate the hepatic mRNA expression of membrane-associated FATPs involved in the uptake of peripherally derived FAs. LPS and cytokines increase the expression of CD36/fatty acid translocase (FAT) while decreasing the mRNA levels of FATP in the liver, suggesting that these proteins may be involved in directing FAs to different intracellular locations (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Fuller J.
      • Grunfeld C.
      Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines.
      ) (Fig. 1). We propose that CD36/FAT transports FAs to cytosol for reesterification, which is enhanced during the APR, whereas FATP transports FAs toward mitochondria for oxidation, which is suppressed during the APR. LPS also decreases the mRNA and protein levels of cytosolic fatty acid binding protein (FABP) in liver, heart, and muscle (
      • Memon R.A.
      • Bass N.M.
      • Moser A.H.
      • Fuller J.
      • Appel R.
      • Grunfeld C.
      • Feingold K.R.
      Down-regulation of liver and heart specific fatty acid binding proteins by endotoxin and cytokines in vivo.
      ). Because FABPs are thought to facilitate the transport of FAs to the site of utilization in the cell, the decrease in FABP may also contribute to decreased FA oxidation during infection. The fact that TNF does not acutely increase the activities of regulatory enzymes of TG synthesis, such as glycerol phosphate acyltransferase and diacylglycerol acyltransferase (
      • Feingold K.R.
      • Adi S.
      • Staprans I.
      • Moser A.H.
      • Neese R.
      • Verdier J.A.
      • Doerrler W.
      • Grunfeld C.
      Diet affects the mechanisms by which TNF stimulates hepatic triglyceride production.
      ), also suggests that the acute increase in TG synthesis is driven by increased FA substrate.
      Mitochondrial ACS converts FA into fatty acyl-CoA, which is subsequently metabolized by mitochondrial carnitine palmitoyl transferase-I (CPT-I) into acylcarnitine. CPT-II subsequently metabolizes acylcarnitine into acyl-CoA, which allows FA entrance into the mitochondria, where it undergoes β-oxidation. Hepatic expression of both CPT-I, the rate-limiting enzyme for mitochondrial FA oxidation, and CPT-II is decreased during sepsis (
      • Barke R.A.
      • Birklid S.
      • Chapin R.B.
      • Roy S.
      • Brady P.S.
      • Brady L.J.
      The effect of surgical treatment following peritoneal sepsis on hepatic gene expression.
      ,
      • Andrejko K.M.
      • Deutschman C.S.
      Altered hepatic gene expression in fecal peritonitis: changes in transcription of gluconeogenic, beta-oxidative, and ureagenic genes.
      ) (Fig. 1). LPS, IL-1, and TNF increase levels of hepatic malonyl-CoA, an allosteric inhibitor of CPT-I, which inhibits the remaining CPT-I, decreasing FA oxidation (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Adi S.
      • Dinarello C.A.
      • Grunfeld C.
      Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis.
      ) (Table 1). IFN-α at high doses increases hepatic malonyl-CoA levels (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Grunfeld C.
      In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.
      ), whereas IFN-γ does not affect hepatic malonyl-CoA levels (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Grunfeld C.
      In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.
      ).
      Given the decrease in FA oxidation, infection is associated with the suppression of hepatic KB production (
      • Beylot M.
      • Guiraud M.
      • Grau G.
      • Bouletreau P.
      Regulation of ketone body flux in septic patients.
      ,
      • Takeyama N.
      • Itoh Y.
      • Kitazawa Y.
      • Tanaka T.
      Altered hepatic mitochondrial fatty acid oxidation and ketogenesis in endotoxic rats.
      ). Serum KB levels are regulated by their rates of synthesis in the liver and utilization in peripheral tissues. Infection decreases KB production through the inhibition of FA oxidation but also likely by increased peripheral KB utilization.
      Various cytokines have different effects on KB metabolism (Table 1). Both TNF and IL-1 acutely decrease serum KB levels in mice (
      • Argiles J.M.
      • Lopez-Soriano F.J.
      • Evans R.D.
      • Williamson D.H.
      Interleukin-1 and lipid metabolism in the rat.
      ,
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Adi S.
      • Dinarello C.A.
      • Grunfeld C.
      Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis.
      ). In the fed state, IL-1 increases hepatic malonyl-CoA levels, inhibiting CPT-I and preventing KB production. During fasting, IL-1 inhibits lipolysis, reducing FA substrate to the liver for KB synthesis (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Adi S.
      • Dinarello C.A.
      • Grunfeld C.
      Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis.
      ). Although TNF increases hepatic malonyl-CoA levels, it stimulates peripheral lipolysis, increasing the flux of FA substrate to the liver, with no net effect on hepatic KB levels (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Adi S.
      • Dinarello C.A.
      • Grunfeld C.
      Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis.
      ), suggesting that TNF decreases serum KB through changes in KB catabolism. IL-6 has no effect on serum KB levels (
      • Nonogaki K.
      • Fuller G.M.
      • Fuentes N.L.
      • Moser A.H.
      • Staprans I.
      • Grunfeld C.
      • Feingold K.R.
      Interleukin-6 stimulates hepatic triglyceride secretion in rats.
      ). IFN-α has biphasic effects: low doses of IFN-α increase serum KB levels by mobilization of FA substrate, whereas higher doses have no effect (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Grunfeld C.
      In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.
      ). IFN-γ stimulates adipose tissue lipolysis, increasing serum and hepatic KB levels (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Doerrler W.
      • Grunfeld C.
      In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.
      ).
      FA uptake and oxidation decrease in heart and skeletal muscle during the APR, shifting their metabolism from FA as the preferred fuel substrate to glucose, whose uptake and utilization are increased (
      • Romanosky A.J.
      • Bagby G.J.
      • Bockman E.L.
      • Spitzer J.J.
      Free fatty acid utilization by skeletal muscle after endotoxin administration.
      ,
      • Romanosky A.J.
      • Bagby G.J.
      • Bockman E.L.
      • Spitzer J.J.
      Increased muscle glucose uptake and lactate release after endotoxin administration.
      ,
      • Lanza-Jacoby S.
      • Feagans K.
      • Tabares A.
      Fatty acid metabolism in the heart during Escherichia coli sepsis in the rat.
      ). This makes more FA available to liver and other tissues, such as those of the immune system. IL-1, but not TNF, decreases LPL activity in the heart (
      • Friedman G.
      • Barak V.
      • Chajek-Shaul T.
      • Etienne J.
      • Treves A.J.
      • Stein O.
      • Stein Y.
      Recombinant human interleukin-1 suppresses lipoprotein lipase activity, but not expression of lipoprotein lipase mRNA in mesenchymal rat heart cell cultures.
      ,
      • Enerback S.
      • Semb H.
      • Tavernier J.
      • Bjursell G.
      • Olivecrona T.
      Tissue-specific regulation of guinea pig lipoprotein lipase: effects of nutritional state and of tumor necrosis factor on mRNA levels in adipose tissue, heart and liver.
      ,
      • Feingold K.R.
      • Marshall M.
      • Gulli R.
      • Moser A.H.
      • Grunfeld C.
      Effect of endotoxin and cytokines on lipoprotein lipase activity in mice.
      ). LPS, TNF, and IL-1 decrease the mRNA expression of FA transport and binding proteins and ACS in heart and muscle (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Fuller J.
      • Grunfeld C.
      Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines.
      ,
      • Memon R.A.
      • Bass N.M.
      • Moser A.H.
      • Fuller J.
      • Appel R.
      • Grunfeld C.
      • Feingold K.R.
      Down-regulation of liver and heart specific fatty acid binding proteins by endotoxin and cytokines in vivo.
      ). It is likely that this coordinated decrease in FA transport and binding proteins and ACS is the mechanism for the decreased uptake and utilization of FA in heart and muscle during infection/inflammation.

      Decreased VLDL clearance

      Infection may also increase serum TG levels by decreasing VLDL clearance. Early in vitro studies showed that TNF decreases LPL expression in cultured adipocytes (
      • Beutler B.
      • Cerami A.
      Cachectin and tumour necrosis factor as two sides of the same biological coin.
      ,
      • Patton J.S.
      • Shepard H.M.
      • Wilking H.
      • Lewis G.
      • Aggarwal B.B.
      • Eessalu T.E.
      • Gavin L.A.
      • Grunfeld C.
      Interferons and tumor necrosis factors have similar catabolic effects on 3T3 L1 cells.
      ). In vivo, however, there is little evidence that hypertriglyceridemia is attributable to decreased LPL activity. First, although TNF reduces LPL activity in epididymal fat pads in rodents (
      • Feingold K.R.
      • Marshall M.
      • Gulli R.
      • Moser A.H.
      • Grunfeld C.
      Effect of endotoxin and cytokines on lipoprotein lipase activity in mice.
      ,
      • Grunfeld C.
      • Gulli R.
      • Moser A.H.
      • Gavin L.A.
      • Feingold K.R.
      Effect of tumor necrosis factor administration in vivo on lipoprotein lipase activity in various tissues of the rat.
      ), this decrease requires many hours, whereas the TNF-induced increase in serum TG levels occurs very rapidly (
      • Feingold K.R.
      • Grunfeld C.
      Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo.
      ). Second, TNF administration does not decrease LPL activity in other adipose tissue sites or in muscle (
      • Chajek-Shaul T.
      • Friedman G.
      • Stein O.
      • Shiloni E.
      • Etienne J.
      • Stein Y.
      Mechanism of the hypertriglyceridemia induced by tumor necrosis factor administration to rats.
      ,
      • Grunfeld C.
      • Gulli R.
      • Moser A.H.
      • Gavin L.A.
      • Feingold K.R.
      Effect of tumor necrosis factor administration in vivo on lipoprotein lipase activity in various tissues of the rat.
      ). Third, TNF-neutralizing antibodies block the LPS-induced increase in serum TG levels in mice but they do not block LPS-induced inhibition of LPL in mouse adipose tissue, again dissociating the LPS-induced increase in serum TGs from changes in LPL activity (
      • Memon R.A.
      • Grunfeld C.
      • Moser A.H.
      • Feingold K.R.
      Tumor necrosis factor mediates the effects of endotoxin on cholesterol and triglyceride metabolism in mice.
      ). Finally, TNF does not decrease the clearance of chylomicrons or VLDL from the circulation, the mechanism by which changes in LPL might influence TG levels (
      • Chajek-Shaul T.
      • Friedman G.
      • Stein O.
      • Shiloni E.
      • Etienne J.
      • Stein Y.
      Mechanism of the hypertriglyceridemia induced by tumor necrosis factor administration to rats.
      ,
      • Feingold K.R.
      • Soued M.
      • Staprans I.
      • Gavin L.A.
      • Donahue M.E.
      • Huang B.J.
      • Moser A.H.
      • Gulli R.
      • Grunfeld C.
      Effect of tumor necrosis factor (TNF) on lipid metabolism in the diabetic rat. Evidence that inhibition of adipose tissue lipoprotein lipase activity is not required for TNF-induced hyperlipidemia.
      ,
      • Feingold K.R.
      • Soued M.
      • Adi S.
      • Staprans I.
      • Shigenaga J.
      • Doerrler W.
      • Moser A.
      • Grunfeld C.
      Tumor necrosis factor-increased hepatic very-low-density lipoprotein production and increased serum triglyceride levels in diabetic rats.
      ).
      Like TNF, IL-1, IL-6, and LIF also require several hours to decrease LPL activity in vivo in mouse adipose tissue (
      • Feingold K.R.
      • Marshall M.
      • Gulli R.
      • Moser A.H.
      • Grunfeld C.
      Effect of endotoxin and cytokines on lipoprotein lipase activity in mice.
      ). IFN-α and IFN-γ increase serum TG levels in humans (
      • Kurzrock R.
      • Rohde M.F.
      • Quesada J.R.
      • Gianturco S.H.
      • Bradley W.A.
      • Sherwin S.A.
      • Gutterman J.U.
      Recombinant gamma interferon induces hypertriglyceridemia and inhibits post-heparin lipase activity in cancer patients.
      ,
      • Olsen E.A.
      • Lichtenstein G.R.
      • Wilkinson W.E.
      Changes in serum lipids in patients with condylomata acuminata treated with interferon alfa-n1 (Wellferon).
      ) but do not increase TG levels in rodents, despite decreasing LPL activity in cultured murine 3T3-L1 fat cells (
      • Doerrler W.
      • Feingold K.R.
      • Grunfeld C.
      Cytokines induce catabolic effects in cultured adipocytes by multiple mechanisms.
      ,
      • Patton J.S.
      • Shepard H.M.
      • Wilking H.
      • Lewis G.
      • Aggarwal B.B.
      • Eessalu T.E.
      • Gavin L.A.
      • Grunfeld C.
      Interferons and tumor necrosis factors have similar catabolic effects on 3T3 L1 cells.
      ), again showing discordance between LPL activity and TG levels.
      There may be a role for the decreased clearance of TG with high doses of LPS. Low doses of LPS enhance hepatic VLDL secretion and increase serum TG levels without affecting TG clearance in rats. In contrast, high doses of LPS inhibit the clearance of TG-rich lipoproteins (
      • Feingold K.R.
      • Staprans I.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Doerrler W.
      • Dinarello C.A.
      • Grunfeld C.
      Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
      ). Moreover, high doses of LPS decrease postheparin plasma LPL activity and LPL activity in adipose tissue and muscle (
      • Feingold K.R.
      • Marshall M.
      • Gulli R.
      • Moser A.H.
      • Grunfeld C.
      Effect of endotoxin and cytokines on lipoprotein lipase activity in mice.
      ).
      LPS and cytokines also decrease apoE mRNA in many tissues, including the liver, and VLDL has lower amounts of apoE during infection (
      • Tripp R.J.
      • Tabares A.
      • Wang H.
      • Lanza-Jacoby S.
      Altered hepatic production of apolipoproteins B and E in the fasted septic rat: factors in the development of hypertriglyceridemia.
      ,
      • Hardardóttir I.
      • Sipe J.
      • Moser A.H.
      • Fielding C.J.
      • Feingold K.R.
      • Grünfeld C.
      LPS and cytokines regulate extra hepatic mRNA levels of apolipoproteins during the acute phase response in Syrian hamsters.
      ,
      • Lanza-Jacoby S.
      • Wong S.H.
      • Tabares A.
      • Baer D.
      • Schneider T.
      Disturbances in the composition of plasma lipoproteins during gram-negative sepsis in the rat.
      ). Because apoE is required for the clearance of TG-rich lipoproteins, decreased apoE could contribute to the delayed clearance observed in rats with infection (
      • Phetteplace H.
      • Maniscalco M.
      • Lanza-Jacoby S.
      The catabolism of apolipoprotein B from very low density lipoprotein and triglyceride-rich lipoprotein remnants in fasted septic rats.
      ).

      Cholesterol metabolism

      There are marked alterations in the metabolism of cholesterol, LDL, HDL, and RCT during infection. LPS and cytokines decrease total serum cholesterol levels in primates, whereas in rodents they increase cholesterol levels by stimulating de novo cholesterol synthesis, decreasing lipoprotein clearance, and decreasing the conversion of cholesterol into bile acids. Such species-specific responses in the APR are common, but the underlying mechanisms responsible for these differences are not yet understood. There are baseline differences in serum cholesterol levels among species, with rodents having low LDL levels and primates having relatively high LDL levels. Baseline levels are often related to the direction of changes in the APR. There are classic positive acute-phase proteins that are expressed at baseline in some species, and they do not increase during the APR in those species.

      Hepatic cholesterol synthesis

      In rodents, LPS stimulates hepatic cholesterol synthesis (
      • Feingold K.R.
      • Hardardottir I.
      • Memon R.
      • Krul E.J.
      • Moser A.H.
      • Taylor J.M.
      • Grunfeld C.
      Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
      ) (Table 2). In contrast to the acute effect of LPS on de novo FA synthesis, the effect of LPS on hepatic cholesterol synthesis is delayed, occurring 16 h after administration (
      • Feingold K.R.
      • Hardardottir I.
      • Memon R.
      • Krul E.J.
      • Moser A.H.
      • Taylor J.M.
      • Grunfeld C.
      Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
      ). LPS stimulates hepatic cholesterol synthesis by increasing the transcription rate, mRNA expression, protein mass, and activity of HMG-CoA reductase, the rate-limiting enzyme in the biosynthetic pathway of cholesterol liver (
      • Feingold K.R.
      • Hardardottir I.
      • Memon R.
      • Krul E.J.
      • Moser A.H.
      • Taylor J.M.
      • Grunfeld C.
      Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
      ,
      • Feingold K.R.
      • Pollock A.S.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      Discordant regulation of proteins of cholesterol metabolism during the acute phase response.
      ). The effect of LPS on HMG-CoA reductase is specific, as the mRNA expression of several other enzymes in the cholesterol synthetic pathway, including HMG-CoA synthase and farnesyl pyrophosphate synthase, which are usually coordinately regulated with HMG-CoA reductase under nutritional or pharmacological manipulations, is not altered by LPS treatment (
      • Yoo J.Y.
      • Desiderio S.
      Innate and acquired immunity intersect in a global view of the acute-phase response.
      ,
      • Feingold K.R.
      • Pollock A.S.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      Discordant regulation of proteins of cholesterol metabolism during the acute phase response.
      ) (Fig. 2). Moreover, LPS still upregulates HMG-CoA reductase mRNA expression when its basal expression is increased by treatment with bile acid binding resins or decreased by feeding a high-cholesterol diet (
      • Feingold K.R.
      • Pollock A.S.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      Discordant regulation of proteins of cholesterol metabolism during the acute phase response.
      ). Thus, the stimulatory effect of LPS on HMG-CoA reductase is independent of dietary regulation and persists over a wide range of basal expression.
      TABLE 2Effects of LPS, LTA, and cytokines on cholesterol metabolism in intact animals
      VariableLPSLTATNFIL-1IL-6IFN-αIFN-γ
      Serum cholesterol↑, ↓
      Primates.
      ↑, ↓
      Primates.
      ↑, ↔
      Primates.
      Hepatic cholesterol

      synthesis
      NDND
      HMG-CoA reductase

      activity
      NDNDND
      LDL receptor protein↓, ↔
      Hamsters.
      ND
      Hamsters.
      Hamsters.
      NDNDND
      Bile acid synthesisNDNDNDND
      Data are for rats and mice unless otherwise noted.
      a Primates.
      b Hamsters.
      Figure thumbnail gr2
      Fig. 2Changes in cholesterol metabolism during the APR. Infection and inflammation are associated with an increase in HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis in the liver. However, there is a decrease in the expression of enzymes downstream of the mevalonate pathway, including squalene synthase. As a result, there is only a modest increase in hepatic cholesterol synthesis, and other mevalonate metabolites are redirected into nonsterol pathways, such as dolichols. FPP, farnesyl pyrophosphate.
      Despite a marked increase in HMG-CoA reductase activity, LPS only produces a modest increase in hepatic cholesterol synthesis and serum cholesterol levels (
      • Feingold K.R.
      • Hardardottir I.
      • Memon R.
      • Krul E.J.
      • Moser A.H.
      • Taylor J.M.
      • Grunfeld C.
      Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
      ). The reason is that LPS produces a decrease in the mRNA expression and activity of squalene synthase (
      • Memon R.A.
      • Shechter I.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin, tumor necrosis factor, and interleukin-1 decrease hepatic squalene synthase activity, protein, and mRNA levels in Syrian hamsters.
      ), the first committed enzyme in cholesterol synthesis located at a branch point in the mevalonate pathway (Fig. 2), and other enzymes downstream of mevalonate pathway (
      • Yoo J.Y.
      • Desiderio S.
      Innate and acquired immunity intersect in a global view of the acute-phase response.
      ). Regulation of squalene synthase plays an important role in regulating the flux of metabolic intermediates to the sterol or nonsterol pathways, which include the synthesis of retinoids, dolichols, ubiquinone, and prenylated proteins. It is likely that the LPS-induced increase in HMG-CoA reductase coupled with a decrease in squalene synthase maintains adequate cholesterol synthesis while redirecting mevalonate metabolites into nonsterol pathways (Fig. 2). Indeed, the synthesis of dolichol phosphate is increased in the liver during inflammation (
      • Mookerjea S.
      • Coolbear T.
      • Sarkar M.L.
      Key role of dolichol phosphate in glycoprotein biosynthesis.
      ,
      • Sarkar M.
      • Mookerjea S.
      Differential effect of inflammation and dexamethasone on dolichol and dolichol phosphate synthesis.
      ). Dolichol is required for the glycosylation of proteins, and the synthesis of several glycosylated plasma proteins is markedly increased in the liver during the APR (
      • Mookerjea S.
      • Coolbear T.
      • Sarkar M.L.
      Key role of dolichol phosphate in glycoprotein biosynthesis.
      ,
      • Sarkar M.
      • Mookerjea S.
      Differential effect of inflammation and dexamethasone on dolichol and dolichol phosphate synthesis.
      ).
      Like LPS, several cytokines, including TNF, IL-1, IL-6, KGF, and NGF, produce a delayed increase in serum cholesterol levels in rodents (
      • Feingold K.R.
      • Grunfeld C.
      Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo.
      ,
      • Feingold K.R.
      • Soued M.
      • Adi S.
      • Staprans I.
      • Neese R.
      • Shigenaga J.
      • Doerrler W.
      • Moser A.
      • Dinarello C.A.
      • Grunfeld C.
      Effect of interleukin-1 on lipid metabolism in the rat. Similarities to and differences from tumor necrosis factor.
      ,
      • Nonogaki K.
      • Fuller G.M.
      • Fuentes N.L.
      • Moser A.H.
      • Staprans I.
      • Grunfeld C.
      • Feingold K.R.
      Interleukin-6 stimulates hepatic triglyceride secretion in rats.
      ,
      • Nonogaki K.
      • Moser A.H.
      • Shigenaga J.
      • Feingold K.R.
      • Grunfeld C.
      Beta-nerve growth factor as a mediator of the acute phase response in vivo.
      ,
      • Nonogaki K.
      • Pan X.M.
      • Moser A.H.
      • Staprans I.
      • Feingold K.R.
      • Grunfeld C.
      Keratinocyte growth factor increases fatty acid mobilization and hepatic triglyceride secretion in rats.
      ) (Table 2). TNF-α, TNF-β, IL-1, and IFN-γ stimulate hepatic cholesterol synthesis in mice, whereas IFN-α and IL-2 have no such effect (
      • Feingold K.R.
      • Soued M.
      • Serio M.K.
      • Moser A.H.
      • Dinarello C.A.
      • Grunfeld C.
      Multiple cytokines stimulate hepatic lipid synthesis in vivo.
      ). Like LPS, both TNF and IL-1 stimulate de novo hepatic cholesterol by increasing the activity and mRNA expression of HMG-CoA reductase (
      • Feingold K.R.
      • Pollock A.S.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      Discordant regulation of proteins of cholesterol metabolism during the acute phase response.
      ,
      • Hardardóttir I.
      • Moser A.H.
      • Memon R.
      • Grünfeld C.
      • Feingold K.R.
      Effects of TNF, IL-1, and the combination of both cytokines on cholesterol metabolism in Syrian hamsters.
      ). TNF and IL-1 decrease squalene synthase activity and mRNA expression (
      • Memon R.A.
      • Shechter I.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin, tumor necrosis factor, and interleukin-1 decrease hepatic squalene synthase activity, protein, and mRNA levels in Syrian hamsters.
      ); they may also divert the flux of mevalonate metabolites into nonsterol pathways during the APR.
      In primates, including humans, infection/inflammation decreases serum cholesterol as a result of decreases in both LDL and HDL cholesterol (
      • Sammalkorpi K.
      • Valtonen V.
      • Kerttula Y.
      • Nikkila E.
      • Taskinen M.R.
      Changes in serum lipoprotein pattern induced by acute infections.
      ,
      • Grunfeld C.
      • Pang M.
      • Doerrler W.
      • Shigenaga J.K.
      • Jensen P.
      • Feingold K.R.
      Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.
      ,
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Ettinger W.H.
      • Miller L.D.
      • Albers J.J.
      • Smith T.K.
      • Parks J.S.
      Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin:cholesterol acyltransferase in cynomolgus monkeys.
      ). LPS, TNF, IL-2, IFN-β, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor decrease serum cholesterol, whereas IL-1 has no effect (
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Ettinger W.H.
      • Miller L.D.
      • Albers J.J.
      • Smith T.K.
      • Parks J.S.
      Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin:cholesterol acyltransferase in cynomolgus monkeys.
      ,
      • Malmendier C.L.
      • Lontie J.F.
      • Sculier J.P.
      • Dubois D.Y.
      Modifications of plasma lipids, lipoproteins and apolipoproteins in advanced cancer patients treated with recombinant interleukin-2 and autologous lymphokine-activated killer cells.
      ,
      • Rosenzweig I.B.
      • Wiebe D.A.
      • Hank J.A.
      • Albers J.J.
      • Adolphson J.L.
      • Borden E.
      • Shrago E.S.
      • Sondel P.M.
      Effects of interleukin-2 (IL-2) on human plasma lipid, lipoprotein, and C-reactive protein.
      ,
      • Spriggs D.R.
      • Sherman M.L.
      • Michie H.
      • Arthur K.A.
      • Imamura K.
      • Wilmore D.
      • Frei 3rd, E.
      • Kufe D.W.
      Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study.
      ,
      • Rosenzweig I.B.
      • Wiebe D.A.
      • Borden E.C.
      • Storer B.
      • Shrago E.S.
      Plasma lipoprotein changes in humans induced by beta-interferon.
      ,
      • Nimer S.D.
      • Champlin R.E.
      • Golde D.W.
      Serum cholesterol-lowering activity of granulocyte-macrophage colony-stimulating factor.
      ,
      • Stoudemire J.B.
      • Garnick M.B.
      Effects of recombinant human macrophage colony-stimulating factor on plasma cholesterol levels.
      ,
      • Ettinger W.H.
      • Miller L.A.
      • Smith T.K.
      • Parks J.S.
      Effect of interleukin-1 alpha on lipoprotein lipids in cynomolgus monkeys: comparison to tumor necrosis factor.
      ). The decrease in cholesterol is accompanied by a reduction in serum apoB levels.
      The mechanism by which infection/inflammation decreases cholesterol levels has not been thoroughly studied in intact primates. Most of the mechanistic studies were performed in vitro using human hepatoma HepG2 cells. IL-1 inhibits cholesterol synthesis and decreases cholesterol and apoB secretion, whereas IL-6 increases cholesterol synthesis but decreases cholesterol secretion (
      • Ettinger W.H.
      • Varma V.K.
      • Sorci-Thomas M.
      • Parks J.S.
      • Sigmon R.C.
      • Smith T.K.
      • Verdery R.B.
      Cytokines decrease apolipoprotein accumulation in medium from Hep G2 cells.
      ). IFN-β also decreases apoB synthesis (
      • Schectman G.
      • Kaul S.
      • Mueller R.A.
      • Borden E.C.
      • Kissebah A.H.
      The effect of interferon on the metabolism of LDLs.
      ).

      LDL clearance

      In rats, LPS significantly inhibits the clearance of LDL from the circulation (
      • Xu N.
      • Nilsson A.
      Endotoxin inhibits catabolism of low density lipoproteins in vivo: an experimental study in the rat.
      ). LPS decreases the expression of hepatic LDL receptor protein (Table 2), but the decrease in protein levels could not be explained by changes in mRNA levels, suggesting that posttranscriptional regulation occurs during the APR (
      • Liao W.
      • Rudling M.
      • Angelin B.
      Endotoxin suppresses mouse hepatic low-density lipoprotein-receptor expression via a pathway independent of the Toll-like receptor 4.
      ). In a rat model of gram-negative sepsis, the rate of apoB degradation is decreased (
      • Phetteplace H.
      • Maniscalco M.
      • Lanza-Jacoby S.
      The catabolism of apolipoprotein B from very low density lipoprotein and triglyceride-rich lipoprotein remnants in fasted septic rats.
      ). In hamsters, however, LPS, IL-1, and TNF either have no effect or produce a slight increase in hepatic LDL receptor mRNA and protein levels (
      • Feingold K.R.
      • Hardardottir I.
      • Memon R.
      • Krul E.J.
      • Moser A.H.
      • Taylor J.M.
      • Grunfeld C.
      Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
      ). In human HepG2 cells, IL-1 and TNF increase LDL receptor activity (
      • Moorby C.D.
      • Gherardi E.
      • Dovey L.
      • Godliman C.
      • Bowyer D.E.
      Transforming growth factor-beta 1 and interleukin-1 beta stimulate LDL receptor activity in Hep G2 cells.
      ,
      • Liao W.
      • Floren C.H.
      Tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells.
      ). The differences may explain the species-specific response in cholesterol metabolism commonly seen during the APR.

      Decreased hepatic cholesterol catabolism and excretion

      Equipped with a number of enzymes and transporters, hepatocytes secrete bile salts, phospholipids, cholesterol, organic anions, and cations into the bile. Cholesterol returned to the liver is primarily metabolized into bile acids, representing the major pathway for the elimination of cholesterol from the body. There are two distinct pathways of bile acid synthesis in mammalian liver (
      • Bjorkhem I.
      • Eggertsen G.
      Genes involved in initial steps of bile acid synthesis.
      ,
      • Russell D.W.
      The enzymes, regulation, and genetics of bile acid synthesis.
      ). The classic or neutral pathway is initiated by microsomal cholesterol 7α-hydroxylase (CYP7A1) that converts cholesterol into 7α-hydroxycholesterol, which is subsequently converted into primary bile acids. The alternative or acidic pathway is initiated by mitochondrial sterol 27-hydroxylase (CYP27A1) that converts cholesterol into 27-hydroxycholesterol, which is then converted into 7α,27-dihydroxycholesterol by oxysterol 7α-hydroxylase (CYP7B1) and subsequently metabolized into primary bile acids. The alternative pathway may contribute as much as 50% to total bile acid synthesis (
      • Bjorkhem I.
      • Eggertsen G.
      Genes involved in initial steps of bile acid synthesis.
      ,
      • Russell D.W.
      The enzymes, regulation, and genetics of bile acid synthesis.
      ). Primary bile acids synthesized in hepatocytes are conjugated with taurine and glycine. At physiological pH, these conjugates exist in the anionic salt form; therefore, they are called bile salts. Secretion of bile salts mediates the solubilization of lipids from the canalicular membrane, resulting in the secretion of biliary phospholipids and cholesterol.
      As polarized cells, hepatocytes contain multiple transporters at the basolateral (sinusoidal) and apical (canalicular) surfaces (
      • Trauner M.
      • Boyer J.L.
      Bile salt transporters: molecular characterization, function, and regulation.
      ). Basolateral bile salt uptake from the portal circulation is primarily mediated by sodium taurocholate-cotransporting protein. Several organic anion-transporting proteins (OATPs), including OATP1, OATP2, and OATP4, are also involved in sodium-independent bile salt uptake. At the canalicular surface, bile salt secretion into the bile duct is mediated by members of the ATP binding cassette (ABC) superfamily. An ABC transporter hydrolyzes intracellular ATP to transport biliary components against the concentration gradient into the bile. The canalicular bile salt export pump (BSEP or ABCB11) secretes monovalent bile salts, whereas multidrug resistance-associated protein-2 (MRP2 or ABCC2) secretes divalent bile salts. Once secreted into the bile, bile salts stimulate the secretion of phospholipids and cholesterol from the canalicular membrane, forming micelles. Multidrug resistance-3 (MDR3 or ABCB4 in humans or MDR2 in rodents) is a phospholipid transporter. Secretion of intact cholesterol into bile is mediated by a heterodimer of two ABC transporters, ABCG5 and ABCG8 (
      • Yu L.
      • Hammer R.E.
      • Li-Hawkins J.
      • Von Bergmann K.
      • Lutjohann D.
      • Cohen J.C.
      • Hobbs H.H.
      • Berge K.E.
      • Horton J.D.
      • Graf G.A.
      • Li W.P.
      • Gerard R.D.
      • Gelissen I.
      • White A.
      Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.
      ,
      • Yu L.
      • Li-Hawkins J.
      • Hammer R.E.
      • Berge K.E.
      • Horton J.D.
      • Cohen J.C.
      • Hobbs H.H.
      • Graf G.A.
      • Li W.P.
      • Gerard R.D.
      • Gelissen I.
      • White A.
      Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol.
      ). These transporters are transcriptionally regulated by a variety of nuclear hormone receptors (
      • Trauner M.
      • Boyer J.L.
      Bile salt transporters: molecular characterization, function, and regulation.
      ).
      LPS and cytokines decrease the catabolism and excretion of cholesterol. In the liver, LPS markedly decreases the mRNA expression and activity of CYP7A1, the rate-limiting enzyme in the classic pathway of bile acid synthesis (
      • Feingold K.R.
      • Spady D.K.
      • Pollock A.S.
      • Moser A.H.
      • Grunfeld C.
      Endotoxin, TNF, and IL-1 decrease cholesterol 7 alpha-hydroxylase mRNA levels and activity.
      ) (Fig. 3). This effect is very rapid, occurring within 90 min of LPS administration, and is sustained for at least 16 h (
      • Feingold K.R.
      • Spady D.K.
      • Pollock A.S.
      • Moser A.H.
      • Grunfeld C.
      Endotoxin, TNF, and IL-1 decrease cholesterol 7 alpha-hydroxylase mRNA levels and activity.
      ). LPS also decreases the mRNA expression and activity of CYP27A1, the rate-limiting enzyme in the alternative pathway of bile acid synthesis, and mRNA levels of CYP7B1 in the liver (
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      In vivo and in vitro regulation of sterol 27-hydroxylase in the liver during the acute phase response. Potential role of hepatocyte nuclear factor-1.
      ) (Fig. 3). The decreases in CYP27A1 and CYP7B1 occur 8–16 h after LPS administration and persist for at least 24 h, suggesting that both the classic and alternative pathways of bile acid synthesis are sequentially downregulated during infection and inflammation. Like LPS, both TNF and IL-1 also decrease hepatic CYP27A1 and CYP7B1 mRNA expression (
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      In vivo and in vitro regulation of sterol 27-hydroxylase in the liver during the acute phase response. Potential role of hepatocyte nuclear factor-1.
      ).
      Figure thumbnail gr3
      Fig. 3Changes in bile acid metabolism during the APR. LPS and cytokines decrease the catabolism and excretion of cholesterol in the liver by decreasing the expression and activities of enzymes in both the classic pathway and the neutral pathway, including cholesterol 7α-hydroxylase (CYP7A1), sterol 27-hydroxylase (CYP27A1), oxysterol 7α-hydroxylase (CYP7B1), and sterol 12α-hydroxylase. LPS also decreases the expression of several protein transporters involved in the canalicular excretion of bile salts, such as bile salt export pump (BSEP) and multidrug resistance-associated protein-2 (MRP2), and those in the hepatocellular uptake of bile salts, including sodium taurocholate-cotransporting protein and organic anion-transporting proteins. Furthermore, LPS decreases the excretion of cholesterol and phospholipids into the bile by downregulating ABCG5/ABCG8 and multidrug resistance-3 (MDR3), respectively.
      Infection is associated with intrahepatic cholestasis that may be attributable to effects on biliary transport. LPS administration in rodents reduces bile salt uptake, bile salt secretion, and bile flow, which are mediated by decreases in the expression of several transporters involved in the hepatocellular uptake, including NCTP, OATP1, and OATP2 (
      • Green R.M.
      • Beier D.
      • Gollan J.L.
      Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents.
      ,
      • Moseley R.H.
      • Wang W.
      • Takeda H.
      • Lown K.
      • Shick L.
      • Ananthanarayanan M.
      • Suchy F.J.
      Effect of endotoxin on bile acid transport in rat liver: a potential model for sepsis-associated cholestasis.
      ,
      • Trauner M.
      • Arrese M.
      • Lee H.
      • Boyer J.L.
      • Karpen S.J.
      Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.
      ,
      • Hartmann G.
      • Cheung A.K.
      • Piquette-Miller M.
      Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia.
      ), and canalicular excretion of bile salts, including BSEP and MRP2 (
      • Hartmann G.
      • Cheung A.K.
      • Piquette-Miller M.
      Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia.
      ,
      • Vos T.A.
      • Hooiveld G.J.
      • Koning H.
      • Childs S.
      • Meijer D.K.
      • Moshage H.
      • Jansen P.L.
      • Muller M.
      Up-regulation of the multidrug resistance genes, Mrp1 and Mdr1b, and down-regulation of the organic anion transporter, Mrp2, and the bile salt transporter, Spgp, in endotoxemic rat liver.
      ). LPS and cytokines also decrease the expression of MDR2 in rats, which mediates phospholipid secretion into bile (
      • Hartmann G.
      • Cheung A.K.
      • Piquette-Miller M.
      Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia.
      ,
      • Tygstrup N.
      • Bangert K.
      • Ott P.
      • Bisgaard H.C.
      Messenger RNA profiles in liver injury and stress: a comparison of lethal and nonlethal rat models.
      ). Moreover, LPS coordinately decreases hepatocyte mRNA levels for ABCG5 and ABCG8, which mediate cholesterol excretion into the bile (
      • Khovidhunkit W.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR.
      ). Thus, biliary secretion of bile salts, phospholipids, and cholesterol are all impaired during infection. Figure 3 summarizes the effect of APR on bile acid metabolism.
      The coordinated downregulation of both pathways of bile acid synthesis during the APR is in contrast to most other situations, including studies in knockout animals, in which during the suppression or absence of one pathway of bile acid synthesis the enzymes of the other pathway are upregulated to compensate for the deficiency. The decreases in the regulatory enzymes of both the classic and alternative pathways of bile acid synthesis as well as the decrease in ABCG5 and ABCG8 induced by LPS and cytokines suggest that during infection the body's need to conserve cholesterol is so essential that all of these pathways are downregulated to limit the elimination of cholesterol from the body. A decrease in cholesterol catabolism would make cholesterol more available for hepatic lipoprotein production.

      Lipoprotein [a]

      Lipoprotein [a] (Lp[a]) is a distinct lipoprotein consisting of an LDL particle attached to apo[a] that is present in primates but not in rodents and most other species (
      • Scanu A.M.
      Lipoprotein(a) and the atherothrombotic process: mechanistic insights and clinical implications.
      ). Lp[a] is cholesterol-rich; increased serum levels have been associated with a higher risk for atherosclerosis. The physiological role of Lp[a] is not known, but it is thought to be involved in wound healing. The structure of apo[a] resembles plasminogen, and apo[a] has been found in the lesions during early stages of wound healing. Alternatively, Lp[a] may act as a scavenger of oxidized lipids, as Lp[a] contains platelet-activating factor acetylhydrolase (PAF-AH) (
      • Karabina S.A.
      • Elisaf M.C.
      • Goudevenos J.
      • Siamopoulos K.C.
      • Sideris D.
      • Tselepis A.D.
      PAF-acetylhydrolase activity of Lp(a) before and during Cu(2+)-induced oxidative modification in vitro.
      ), an enzyme that inactivates PAF and oxidized lipids.
      Whether Lp[a] is an acute-phase reactant is unclear. Some studies showed that levels of Lp[a] are increased during stress (
      • Maeda S.
      • Abe A.
      • Seishima M.
      • Makino K.
      • Noma A.
      • Kawade M.
      Transient changes of serum lipoprotein(a) as an acute phase protein.
      ,
      • Wallberg-Jonsson S.
      • Uddhammar A.
      • Dahlen G.
      • Rantapaa-Dahlqvist S.
      Lipoprotein(a) in relation to acute phase reaction in patients with rheumatoid arthritis and polymyalgia rheumatica.
      ), whereas others reported no changes or a reduction (
      • Andreassen A.K.
      • Berg K.
      • Torsvik H.
      Changes in Lp(a) lipoprotein and other plasma proteins during acute myocardial infarction.
      ,
      • Mooser V.
      • Berger M.M.
      • Tappy L.
      • Cayeux C.
      • Marcovina S.M.
      • Darioli R.
      • Nicod P.
      • Chiolero R.
      Major reduction in plasma Lp(a) levels during sepsis and burns.
      ). These conflicting data may be attributable to the specificity of the assays used to measure Lp[a] levels or to interindividual variation in plasma Lp[a] levels in the population.

      HDL metabolism and decreased RCT

      During infection and inflammation, there is a marked decrease in serum levels of HDL and apoA-I (
      • Sammalkorpi K.
      • Valtonen V.
      • Kerttula Y.
      • Nikkila E.
      • Taskinen M.R.
      Changes in serum lipoprotein pattern induced by acute infections.
      ,
      • Grunfeld C.
      • Pang M.
      • Doerrler W.
      • Shigenaga J.K.
      • Jensen P.
      • Feingold K.R.
      Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.
      ,
      • Feingold K.R.
      • Hardardottir I.
      • Memon R.
      • Krul E.J.
      • Moser A.H.
      • Taylor J.M.
      • Grunfeld C.
      Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
      ,
      • Cabana V.G.
      • Siegel J.N.
      • Sabesin S.M.
      Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins.
      ). Furthermore, circulating HDL during infection, known as acute-phase HDL, has different characteristics from normal HDL. Acute-phase HDL is larger than normal HDL3, its radius extending into the HDL2 range, but it has a density comparable to that of HDL3 (
      • Clifton P.M.
      • Mackinnon A.M.
      • Barter P.J.
      Effects of serum amyloid A protein (SAA) on composition, size, and density of high density lipoproteins in subjects with myocardial infarction.
      ). Acute-phase HDL is depleted in cholesteryl ester but enriched in free cholesterol, TG, and free FAs (
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Ettinger W.H.
      • Miller L.D.
      • Albers J.J.
      • Smith T.K.
      • Parks J.S.
      Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin:cholesterol acyltransferase in cynomolgus monkeys.
      ,
      • Feingold K.R.
      • Hardardottir I.
      • Memon R.
      • Krul E.J.
      • Moser A.H.
      • Taylor J.M.
      • Grunfeld C.
      Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
      ,
      • Clifton P.M.
      • Mackinnon A.M.
      • Barter P.J.
      Effects of serum amyloid A protein (SAA) on composition, size, and density of high density lipoproteins in subjects with myocardial infarction.
      ,
      • Cabana V.G.
      • Lukens J.R.
      • Rice K.S.
      • Hawkins T.J.
      • Getz G.S.
      HDL content and composition in acute phase response in three species: triglyceride enrichment of HDL a factor in its decrease.
      ,
      • Pruzanski W.
      • Stefanski E.
      • de Beer F.C.
      • de Beer M.C.
      • Ravandi A.
      • Kuksis A.
      Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins.
      ). The phospholipid content of acute-phase HDL was increased in some studies (
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Feingold K.R.
      • Hardardottir I.
      • Memon R.
      • Krul E.J.
      • Moser A.H.
      • Taylor J.M.
      • Grunfeld C.
      Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
      ) but decreased in others (
      • Cabana V.G.
      • Siegel J.N.
      • Sabesin S.M.
      Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins.
      ,
      • Clifton P.M.
      • Mackinnon A.M.
      • Barter P.J.
      Effects of serum amyloid A protein (SAA) on composition, size, and density of high density lipoproteins in subjects with myocardial infarction.
      ). In patients who underwent bypass surgery, acute-phase HDL had the same phospholipid-neutral lipid ratio, a decrease in phosphatidylethanolamine and phosphatidylinositol, and an increase in isoprostane-containing phosphatidylcholine and lysophosphatidylcholine (LPC) (
      • Pruzanski W.
      • Stefanski E.
      • de Beer F.C.
      • de Beer M.C.
      • Ravandi A.
      • Kuksis A.
      Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins.
      ). In humans, there was a decrease in HDL sphingomyelin content (
      • Pruzanski W.
      • Stefanski E.
      • de Beer F.C.
      • de Beer M.C.
      • Ravandi A.
      • Kuksis A.
      Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins.
      ), but an increase was observed in hamsters (
      • Memon R.A.
      • Holleran W.M.
      • Moser A.H.
      • Seki T.
      • Uchida Y.
      • Fuller J.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin.
      ).
      The hallmark of acute-phase HDL is an increase in apoSAA (
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Cabana V.G.
      • Siegel J.N.
      • Sabesin S.M.
      Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins.
      ,
      • Clifton P.M.
      • Mackinnon A.M.
      • Barter P.J.
      Effects of serum amyloid A protein (SAA) on composition, size, and density of high density lipoproteins in subjects with myocardial infarction.
      ,
      • Hoffman J.S.
      • Benditt E.P.
      Changes in high density lipoprotein content following endotoxin administration in the mouse. Formation of serum amyloid protein-rich subfractions.
      ,
      • Lindhorst E.
      • Young D.
      • Bagshaw W.
      • Hyland M.
      • Kisilevsky R.
      Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse.
      ) and a decrease in apoA-I content (
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Cabana V.G.
      • Siegel J.N.
      • Sabesin S.M.
      Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins.
      ,
      • Pruzanski W.
      • Stefanski E.
      • de Beer F.C.
      • de Beer M.C.
      • Ravandi A.
      • Kuksis A.
      Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins.
      ,
      • Lindhorst E.
      • Young D.
      • Bagshaw W.
      • Hyland M.
      • Kisilevsky R.
      Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse.
      ) (Table 3). The content of apoA-II and apoCs is decreased (
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Cabana V.G.
      • Siegel J.N.
      • Sabesin S.M.
      Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins.
      ,
      • Lindhorst E.
      • Young D.
      • Bagshaw W.
      • Hyland M.
      • Kisilevsky R.
      Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse.
      ,
      • Sakaguchi S.
      Metabolic disorders of serum lipoproteins in endotoxin-poisoned mice: the role of high density lipoprotein (HDL) and triglyceride-rich lipoproteins.
      ), whereas apoE is found to be increased in some studies (
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Barlage S.
      • Frohlich D.
      • Bottcher A.
      • Jauhiainen M.
      • Muller H.P.
      • Noetzel F.
      • Rothe G.
      • Schutt C.
      • Linke R.P.
      • Lackner K.J.
      • Ehnholm C.
      • Schmitz G.
      ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response.
      ) but decreased in others (
      • Lindhorst E.
      • Young D.
      • Bagshaw W.
      • Hyland M.
      • Kisilevsky R.
      Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse.
      ). HDL-associated apoJ is increased during inflammation and infection in rodents and humans (
      • Hardardóttir I.
      • Kunitake S.T.
      • Moser A.H.
      • Doerrler W.T.
      • Rapp J.H.
      • Grünfeld C.
      • Feingold K.R.
      Endotoxin and cytokines increase hepatic messenger RNA levels and serum concentrations of apolipoprotein J (clusterin) in Syrian hamsters.
      ,
      • Van Lenten B.J.
      • Hama S.Y.
      • de Beer F.C.
      • Stafforini D.M.
      • McIntyre T.M.
      • Prescott S.M.
      • La Du B.N.
      • Fogelman A.M.
      • Navab M.
      Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures.
      ,
      • Van Lenten B.J.
      • Wagner A.C.
      • Nayak D.P.
      • Hama S.
      • Navab M.
      • Fogelman A.M.
      High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection.
      ). In contrast, several other proteins, including LCAT (
      • Auerbach B.J.
      • Parks J.S.
      Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin:cholesterol acyltransferase and lipase deficiency.
      ,
      • Ettinger W.H.
      • Miller L.D.
      • Albers J.J.
      • Smith T.K.
      • Parks J.S.
      Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin:cholesterol acyltransferase in cynomolgus monkeys.
      ,
      • Ly H.
      • Francone O.L.
      • Fielding C.J.
      • Shigenaga J.K.
      • Moser A.H.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin and TNF lead to reduced plasma LCAT activity and decreased hepatic LCAT mRNA levels in Syrian hamsters.
      ), cholesteryl ester transfer protein (CETP) (
      • Masucci-Magoulas L.
      • Moulin P.
      • Jiang X.C.
      • Richardson H.
      • Walsh A.
      • Breslow J.L.
      • Tall A.
      Decreased cholesteryl ester transfer protein (CETP) mRNA and protein and increased high density lipoprotein following lipopolysaccharide administration in human CETP transgenic mice.
      ,
      • Hardardóttir I.
      • Moser A.H.
      • Fuller J.
      • Fielding C.
      • Feingold K.
      • Grünfeld C.
      Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA levels of cholesteryl ester transfer protein in Syrian hamsters.
      ), hepatic lipase (HL) (
      • Feingold K.R.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      Endotoxin and interleukin-1 decrease hepatic lipase mRNA levels.
      ), and paraoxonase 1 (PON1) (
      • Van Lenten B.J.
      • Hama S.Y.
      • de Beer F.C.
      • Stafforini D.M.
      • McIntyre T.M.
      • Prescott S.M.
      • La Du B.N.
      • Fogelman A.M.
      • Navab M.
      Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures.
      ,
      • Feingold K.R.
      • Memon R.A.
      • Moser A.H.
      • Grunfeld C.
      Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response.
      ), are decreased during the APR. The activity of HDL-associated plasma PAF-AH is acutely increased during inflammation in several rodent species (
      • Memon R.A.
      • Fuller J.
      • Moser A.H.
      • Feingold K.R.
      • Grunfeld C.
      In vivo regulation of plasma platelet-activating factor acetylhydrolase during the acute phase response.
      ), but a late decrease has also been reported in rabbits and mice (
      • Van Lenten B.J.
      • Hama S.Y.
      • de Beer F.C.
      • Stafforini D.M.
      • McIntyre T.M.
      • Prescott S.M.
      • La Du B.N.
      • Fogelman A.M.
      • Navab M.
      Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures.
      ,
      • Van Lenten B.J.
      • Wagner A.C.
      • Nayak D.P.
      • Hama S.
      • Navab M.
      • Fogelman A.M.
      High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection.
      ). Phospholipid transfer protein (PLTP) is decreased in rats injected with LPS (
      • Jiang X.C.
      • Bruce C.
      Regulation of murine plasma phospholipid transfer protein activity and mRNA levels by lipopolysaccharide and high cholesterol diet.
      ), but data in humans are conflicting (
      • Barlage S.
      • Frohlich D.
      • Bottcher A.
      • Jauhiainen M.
      • Muller H.P.
      • Noetzel F.
      • Rothe G.
      • Schutt C.
      • Linke R.P.
      • Lackner K.J.
      • Ehnholm C.
      • Schmitz G.
      ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response.
      ,
      • Hudgins L.C.
      • Parker T.S.
      • Levine D.M.
      • Gordon B.R.
      • Saal S.D.
      • Jiang X.C.
      • Seidman C.E.
      • Tremaroli J.D.
      • Lai J.
      • Rubin A.L.
      A single intravenous dose of endotoxin rapidly alters serum lipoproteins and lipid transfer proteins in normal volunteers.
      ). Finally, secretory phospholipase A2 (sPLA2), a phospholipase enzyme that hydrolyzes phospholipids in HDL, and LPS-binding protein (LBP) are markedly induced during infection and inflammation (
      • Pruzanski W.
      • Vadas P.
      • Browning J.
      Secretory non-pancreatic group II phospholipase A2: role in physiologic and inflammatory processes.
      ). SAA-rich HDL particles that are devoid of apoA-I have also been reported (
      • Cabana V.G.
      • Reardon C.A.
      • Wei B.
      • Lukens J.R.
      • Getz G.S.
      SAA-only HDL formed during the acute phase response in apoA-I+/+ and apoA-I−/− mice.
      ). We recently found that apoA-IV and apoA-V levels are increased in acute-phase HDL (our unpublished observations).
      TABLE 3Changes in proteins involved in HDL metabolism during infection and inflammation
      ProteinsEffects
      Increased
       Apolipoprotein serum amyloid ADecreases cholesterol uptake by hepatocytes; increases cholesterol uptake into macrophages
       Secretory phospholipase A2Decreases phospholipid content of HDL and impairs cholesterol removal from cells
       ApoJNot known
       PAF-AHIncreases lysophosphatidylcholine production
       LPS binding proteinIncreases neutralization of endotoxin by HDL
       ApoEIncreases cholesterol delivery to cells; redirects endotoxin from macrophages to hepatocytes
       ApoA-IVDecreases endotoxin-induced stimulation of monocytes
       ApoA-VNot known
       CeruloplasminEnhances LDL oxidation
      Decreased
       ApoA-IImpairs cholesterol removal from cells
       ApoA-IINot known
       LCATImpairs cholesterol removal from cells
       CETPImpairs cholesterol transfer to apoB-containing lipoproteins
       Hepatic lipaseDecreases pre-β HDL generation
       Paraoxonase 1Decreases the ability of HDL to protect against LDL oxidation
       TransferrinDecreases the ability of HDL to protect against LDL oxidation
      apoJ, apolipoprotein J; CETP, cholesteryl ester transfer protein; PAF-AH, platelet-activating factor acetylhydrolase.
      Although it is well established that infection and inflammation are associated with a reduction in serum HDL and apoA-I levels, the exact mechanism has not yet been established. Because apoSAA can displace apoA-I from HDL (
      • Husebekk A.
      • Skogen B.
      • Husby G.
      High-density lipoprotein has different binding capacity for different apoproteins. The amyloidogenic apoproteins are easier to displace from high-density lipoprotein.
      ,
      • Coetzee G.A.
      • Strachan A.F.
      • van der Westhuyzen D.R.
      • Hoppe H.C.
      • Jeenah M.S.
      • de Beer F.C.
      Serum amyloid A-containing human high density lipoprotein 3. Density, size, and apolipoprotein composition.
      ) and apoSAA-rich HDL particles are rapidly cleared from the circulation (
      • Hoffman J.S.
      • Benditt E.P.
      Plasma clearance kinetics of the amyloid-related high density lipoprotein apoprotein, serum amyloid protein (apoSAA), in the mouse. Evidence for rapid apoSAA clearance.
      ), it has been assumed that the several-fold increase in apoSAA content in HDL is the mechanism for the decrease in apoA-I and HDL levels. However, we have shown that the decrease in HDL is very rapid, occurring before the increase in SAA (
      • Ly H.
      • Francone O.L.
      • Fielding C.J.
      • Shigenaga J.K.
      • Moser A.H.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin and TNF lead to reduced plasma LCAT activity and decreased hepatic LCAT mRNA levels in Syrian hamsters.
      ). Furthermore, a study in mice in which apoSAA levels were markedly increased to levels comparable to those seen in infection found no changes in HDL cholesterol or apoA-I levels (
      • Hosoai H.
      • Webb N.R.
      • Glick J.M.
      • Tietge U.J.
      • Purdom M.S.
      • de Beer F.C.
      • Rader D.J.
      Expression of serum amyloid A protein in the absence of the acute phase response does not reduce HDL cholesterol or apoA-I levels in human apoA-I transgenic mice.
      ). Thus, high levels of SAA per se do not decrease HDL or apoA-I levels in the absence of the other changes that occur during infection and inflammation.
      An increase in sPLA2 has also been proposed to contribute to the reduction in HDL during infection/inflammation. Mice overexpressing sPLA2 have reduced HDL concentrations (
      • de Beer F.C.
      • de Beer M.C.
      • van der Westhuyzen D.R.
      • Castellani L.W.
      • Lusis A.J.
      • Swanson M.E.
      • Grass D.S.
      Secretory non-pancreatic phospholipase A2: influence on lipoprotein metabolism.
      ), and HDL from these mice is catabolized more rapidly than HDL from normal mice (
      • Tietge U.J.
      • Maugeais C.
      • Cain W.
      • Grass D.
      • Glick J.M.
      • de Beer F.C.
      • Rader D.J.
      Overexpression of secretory phospholipase A(2) causes rapid catabolism and altered tissue uptake of high density lipoprotein cholesteryl ester and apolipoprotein A-I.
      ). Although apoSAA is known to activate sPLA2, overexpression of SAA in addition to sPLA2 does not cause a greater reduction in the levels of HDL or apoA-I (
      • Tietge U.J.
      • Maugeais C.
      • Lund-Katz S.
      • Grass D.
      • DeBeer F.C.
      • Rader D.J.
      Human secretory phospholipase A(2) mediates decreased plasma levels of HDL cholesterol and apoA-I in response to inflammation in human apoA-I transgenic mice.
      ), further suggesting that the reduction of HDL during infection is not caused by an increase in apoSAA.
      Endothelial lipase (EL) has been shown to regulate HDL metabolism (
      • Jaye M.
      • Lynch K.J.
      • Krawiec J.
      • Marchadier D.
      • Maugeais C.
      • Doan K.
      • South V.
      • Amin D.
      • Perrone M.
      • Rader D.J.
      A novel endothelial-derived lipase that modulates HDL metabolism.
      ,
      • Ma K.
      • Cilingiroglu M.
      • Otvos J.D.
      • Ballantyne C.M.
      • Marian A.J.
      • Chan L.
      Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism.
      ,
      • Ishida T.
      • Choi S.
      • Kundu R.K.
      • Hirata K.
      • Rubin E.M.
      • Cooper A.D.
      • Quertermous T.
      Endothelial lipase is a major determinant of HDL level.
      ). EL is synthesized by the endothelial cells and possesses phospholipase A-I activity. Overexpression of EL reduces HDL cholesterol levels (
      • Jaye M.
      • Lynch K.J.
      • Krawiec J.
      • Marchadier D.
      • Maugeais C.
      • Doan K.
      • South V.
      • Amin D.
      • Perrone M.
      • Rader D.J.
      A novel endothelial-derived lipase that modulates HDL metabolism.
      ), whereas inhibition of EL increases HDL levels (
      • Jin W.
      • Millar J.S.
      • Broedl U.
      • Glick J.M.
      • Rader D.J.
      Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo.
      ). Treatment of cultured endothelial cells with TNF-α or IL-1β has been shown to increase the expression of EL (
      • Jin W.
      • Sun G.S.
      • Marchadier D.
      • Octtaviani E.
      • Glick J.M.
      • Rader D.J.
      Endothelial cells secrete triglyceride lipase and phospholipase activities in response to cytokines as a result of endothelial lipase.
      ). If similar effects occur in vivo, it may provide another mechanism for the reduction in HDL levels during infection.
      The decrease in LCAT activity during infection may decrease HDL cholesterol levels caused by impaired esterification, similar to what is found in humans or animals with mutations in the LCAT gene (
      • Kuivenhoven J.A.
      • Pritchard H.
      • Hill J.
      • Frohlich J.
      • Assmann G.
      • Kastelein J.
      The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes.
      ). The decrease in HL may reduce pre-β HDL generation. Moreover, TG enrichment of HDL during infection may lead to the rapid clearance of apoA-I (
      • Lamarche B.
      • Uffelman K.D.
      • Carpentier A.
      • Cohn J.S.
      • Steiner G.
      • Barrett P.H.
      • Lewis G.F.
      Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men.
      ). Which of these changes contributes to the reduction of HDL and apoA-I during the APR is not yet established, but none accounts for the early decrease.
      HDL metabolism is tightly linked to RCT, a process by which cholesterol is removed from peripheral cells and transported to the liver for metabolism and/or excretion (
      • Fielding C.J.
      • Fielding P.E.
      Molecular physiology of reverse cholesterol transport.
      ,
      • von Eckardstein A.
      • Nofer J.R.
      • Assmann G.
      High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport.
      ). Several HDL-associated proteins and a number of cell surface receptors play a key role in RCT (Fig. 4). ApoA-I on HDL and ABCA1 in the plasma membrane are required for apolipoprotein-mediated cholesterol efflux. Subsequently, LCAT, which converts free cholesterol on HDL into cholesteryl ester, assists in cholesterol efflux by an aqueous diffusion mechanism. CETP then mediates the exchange of cholesteryl ester in HDL for TG in TG-rich lipoproteins. PLTP transfers phospholipids from TG-rich lipoproteins into HDL and promotes the remodeling of HDL. HL hydrolyzes TG and phospholipids in large α-HDL, generating small pre-β HDL particles that are efficient acceptors of cholesterol from plasma membrane. In the liver, scavenger receptor class B type I (SR-BI) plays a key role in the selective uptake of cholesteryl ester, whereas the β-chain of ATP synthase mediates endocytosis of HDL particles.
      Figure thumbnail gr4
      Fig. 4Changes in reverse cholesterol transport during the APR. LPS and cytokines decrease ABCA1 and cholesterol efflux from peripheral cells to HDL. LPS also decreases several enzymes involved in HDL metabolism, including LCAT, cholesteryl ester transfer protein (CETP), and hepatic lipase (HL). In addition, LPS and cytokines downregulate hepatic scavenger receptor class B type I (SR-BI), resulting in a decrease in cholesteryl ester (CE) uptake into the liver. FC, free cholesterol; LDL-R, LDL receptor; LRP, LDL receptor related protein; PLTP, phospholipid transfer protein.
      During infection and inflammation, there is a reduction in RCT attributable to multiple changes at each step in the pathway (Fig. 4). ABCA1 mRNA and protein levels in macrophages are decreased by LPS and cytokines (
      • Khovidhunkit W.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR.
      ,
      • Baranova I.
      • Vishnyakova T.
      • Bocharov A.
      • Chen Z.
      • Remaley A.T.
      • Stonik J.
      • Eggerman T.L.
      • Patterson A.P.
      Lipopolysaccharide down regulates both scavenger receptor B1 and ATP binding cassette transporter A1 in RAW cells.
      ), impairing cholesterol efflux from cells. The decreases in apoA-I, HDL, and LCAT impair the acceptance of cellular cholesterol (
      • Khovidhunkit W.
      • Shigenaga J.K.
      • Moser A.H.
      • Feingold K.R.
      • Grunfeld C.
      Cholesterol efflux by acute-phase high density lipoprotein. Role of lecithin:cholesterol acyltransferase.
      ). The decrease in CETP activity limits the transfer of cholesteryl ester to TG-rich lipoproteins, further retarding the RCT pathway (
      • Hardardóttir I.
      • Moser A.H.
      • Fuller J.
      • Fielding C.
      • Feingold K.
      • Grünfeld C.
      Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA levels of cholesteryl ester transfer protein in Syrian hamsters.
      ). HL activity is decreased (
      • Feingold K.R.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      Endotoxin and interleukin-1 decrease hepatic lipase mRNA levels.
      ), which would reduce the generation of pre-β HDL particles. In addition, during the APR, mRNA expression and protein levels of SR-BI in the liver are markedly decreased, which is accompanied by decreased cholesteryl ester uptake into hepatocytes (
      • Khovidhunkit W.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Regulation of scavenger receptor class B type I in hamster liver and Hep3B cells by endotoxin and cytokines.
      ). Therefore, during infection and inflammation, RCT is affected at the level of cholesterol removal from cells, transfer among particles, and uptake by the liver.

      Sphingolipid metabolism

      Sphingolipids such as ceramide and sphingomyelin are important constituents of plasma membranes. Glycosphingolipids (GSLs) are complex sphingolipids that contain a hydrophobic ceramide moiety and a hydrophilic oligosaccharide residue. Both sphingolipids and GSLs are components of plasma lipoproteins and are involved in several biological processes, including cell recognition and proliferation, signal transduction, interaction with bacterial toxins, and modulation of the immune response.
      The metabolism of sphingolipids and GSLs is altered during infection and inflammation. LPS stimulates hepatic ceramide and sphingomyelin synthesis by increasing the mRNA expression and activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme in sphingolipid synthesis that catalyzes the condensation of serine with palmitoyl-CoA (
      • Memon R.A.
      • Holleran W.M.
      • Moser A.H.
      • Seki T.
      • Uchida Y.
      • Fuller J.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin.
      ) (Fig. 5). LPS increases the transcription rate, mRNA expression, and activity of glucosylceramide (GlcCer) synthase, the first committed enzyme in the GSL synthesis pathway, in the liver (
      • Memon R.A.
      • Holleran W.M.
      • Uchida Y.
      • Moser A.H.
      • Ichikawa S.
      • Hirabayashi Y.
      • Grunfeld C.
      • Feingold K.R.
      Regulation of glycosphingolipid metabolism in liver during the acute phase response.
      ). GlcCer is the precursor of all neutral GSLs as well as sialic acid-containing acidic GSLs or gangliosides. The LPS-induced increase in GlcCer expression occurs earlier than the increase in SPT mRNA levels. It is possible that the increase in hepatic GlcCer production during the APR is the primary event, which then signals for more substrate, resulting in the induction of SPT and subsequent increase in ceramide synthesis. This hypothesis is supported by the fact that steady-state levels of GlcCer and its distal metabolites, including ceramide trihexoside and ganglioside GM3, are increased in the liver after LPS treatment (
      • Memon R.A.
      • Holleran W.M.
      • Uchida Y.
      • Moser A.H.
      • Ichikawa S.
      • Hirabayashi Y.
      • Grunfeld C.
      • Feingold K.R.
      Regulation of glycosphingolipid metabolism in liver during the acute phase response.
      ), whereas in contrast, the content of ceramide, the substrate for GlcCer synthesis, is decreased in the liver despite the increase in SPT (
      • Memon R.A.
      • Holleran W.M.
      • Uchida Y.
      • Moser A.H.
      • Ichikawa S.
      • Hirabayashi Y.
      • Grunfeld C.
      • Feingold K.R.
      Regulation of glycosphingolipid metabolism in liver during the acute phase response.
      ). Like LPS, TNF and IL-1 also increase both SPT and GlcCer mRNA expression in the liver, suggesting that these cytokines mediate the LPS effect (
      • Memon R.A.
      • Holleran W.M.
      • Moser A.H.
      • Seki T.
      • Uchida Y.
      • Fuller J.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin.
      ,
      • Memon R.A.
      • Holleran W.M.
      • Uchida Y.
      • Moser A.H.
      • Ichikawa S.
      • Hirabayashi Y.
      • Grunfeld C.
      • Feingold K.R.
      Regulation of glycosphingolipid metabolism in liver during the acute phase response.
      ).
      Figure thumbnail gr5
      Fig. 5Changes in sphingolipid metabolism during the APR. LPS and cytokines stimulate ceramide (Cer) and sphingomyelin (SM) synthesis in the liver by increasing the expression and activity of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. LPS also increases the activity of glucosylceramide (GC) synthase, the first committed enzyme in the glycosphingolipid synthesis pathway. As a result, lipoproteins are enriched with ceramide, sphingomyelin, and glycosphingolipids. In addition, LPS and cytokines increase the activity of secretory sphingomyelinase (SMase) in the serum, resulting in increased levels of ceramide in serum. 1-P, 1-phosphate.
      Likely as a consequence of the LPS-induced increase in hepatic sphingolipid synthesis, all lipoprotein fractions isolated from LPS-treated animals contain significantly higher levels of ceramide, sphingomyelin, and GlcCer (
      • Memon R.A.
      • Holleran W.M.
      • Moser A.H.
      • Seki T.
      • Uchida Y.
      • Fuller J.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin.
      ). An increase in ceramide content in LDL may enhance the susceptibility of LDL toward aggregation.
      LPS also upregulates the mRNA expression and activities of SPT and GlcCer synthase in extrahepatic tissues, including spleen and kidney (
      • Memon R.A.
      • Holleran W.M.
      • Uchida Y.
      • Moser A.H.
      • Grunfeld C.
      • Feingold K.R.
      Regulation of sphingolipid and glycosphingolipid metabolism in extrahepatic tissues by endotoxin.
      ). The content of ceramide in spleen or kidney, however, is not increased, suggesting that newly synthesized ceramide is used as a substrate to increase GlcCer synthesis (
      • Memon R.A.
      • Holleran W.M.
      • Uchida Y.
      • Moser A.H.
      • Grunfeld C.
      • Feingold K.R.
      Regulation of sphingolipid and glycosphingolipid metabolism in extrahepatic tissues by endotoxin.
      ). Specific GSLs are ligands for a T-cell receptor expressed on natural killer T-lymphocytes, and GSLs stimulate the proliferation of specific subsets of lymphocytes (
      • Kawano T.
      • Cui J.
      • Koezuka Y.
      • Toura I.
      • Kaneko Y.
      • Motoki K.
      • Ueno H.
      • Nakagawa R.
      • Sato H.
      • Kondo E.
      • Koseki H.
      • Taniguchi M.
      CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides.
      ). One can speculate that the LPS-induced increase in GSL content of these tissues is used to regulate cellular proliferation and modulate the immune response.
      In addition to activating the enzymes that synthesize sphingolipids and GSLs, LPS and cytokines also induce enzymes involved in the hydrolysis of sphingolipids (Fig. 5). Treatment with LPS, TNF, or IL-1 acutely increases the serum activity of secretory sphingomyelinase (
      • Wong M.L.
      • Xie B.
      • Beatini N.
      • Phu P.
      • Marathe S.
      • Johns A.
      • Gold P.W.
      • Hirsch E.
      • Williams K.J.
      • Licinio J.
      • Tabas I.
      Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: a possible link between inflammatory cytokines and atherogenesis.
      ). Serum ceramide levels are increased in animals treated with LPS and in patients with sepsis (
      • Memon R.A.
      • Holleran W.M.
      • Moser A.H.
      • Seki T.
      • Uchida Y.
      • Fuller J.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin.
      ,
      • Delogu G.
      • Famularo G.
      • Amati F.
      • Signore L.
      • Antonucci A.
      • Trinchieri V.
      • Di Marzio L.
      • Cifone M.G.
      Ceramide concentrations in septic patients: a possible marker of multiple organ dysfunction syndrome.
      ,
      • Drobnik W.
      • Liebisch G.
      • Audebert F.X.
      • Frohlich D.
      • Gluck T.
      • Vogel P.
      • Rothe G.
      • Schmitz G.
      Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients.
      ). The APR also activates ceramide-metabolizing enzymes. IL-1 activates both neutral and acid ceramidases in cultured rat hepatocytes, resulting in increased formation of sphingosine (
      • Nikolova-Karakashian M.
      • Morgan E.T.
      • Alexander C.
      • Liotta D.C.
      • Merrill Jr., A.H.
      Bimodal regulation of ceramidase by interleukin-1beta. Implications for the regulation of cytochrome p450 2C11.
      ), whereas in cultured endothelial cells, TNF induces sphingosine kinase activity and increases the formation of sphingosine-1-phosphate (
      • Xia P.
      • Gamble J.R.
      • Rye K.A.
      • Wang L.
      • Hii C.S.
      • Cockerill P.
      • Khew-Goodall Y.
      • Bert A.G.
      • Barter P.J.
      • Vadas M.A.
      Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway.
      ). These studies suggest that several enzymes involved either in the de novo synthesis of ceramide and its downstream metabolites or in the hydrolysis of ceramide are induced by LPS and cytokines. Because ceramide and its metabolites are involved in signal transduction and cellular regulation, particularly in cells of the immune system, it makes sense that several anabolic and catabolic pathways of sphingolipid metabolism are induced during infection and inflammation to maintain a delicate balance between ceramide and its metabolites in the cell. Figure 5 summarizes the effects of LPS and APR-inducing cytokines on sphingolipid and GSL metabolism.

      ROLE OF NUCLEAR HORMONE RECEPTORS IN THE REGULATION OF LIPID METABOLISM DURING INFECTION AND INFLAMMATION

      Nuclear hormone receptors and lipid metabolism

      Most, if not all, of the changes in lipid metabolism that are induced by infection and inflammation are attributable to changes in gene transcription (
      • Hardardóttir I.
      • Grunfeld C.
      • Feingold K.R.
      Effects of endotoxin on lipid metabolism.
      ). The mechanisms by which gene transcription is increased during the APR have been extensively studied. Class 1 positive acute-phase proteins are increased by IL-1-type cytokines, whereas the IL-6 family of cytokines increase class 2 positive acute-phase proteins (
      • Baumann H.
      • Prowse K.R.
      • Marinkovic S.
      • Won K.A.
      • Jahreis G.P.
      Stimulation of hepatic acute phase response by cytokines and glucocorticoids.
      ,
      • Kishimoto T.
      • Taga T.
      • Akira S.
      Cytokine signal transduction.
      ). Activation of nuclear factor κB (NF-κB) and nuclear factor interleukin-6 (NF-IL-6) mediates IL-1-stimulated increases in acute-phase protein transcription, whereas activation of NF-IL-6 and the Janus kinase-signal transducers and activators of transcription pathway mediates IL-6 family stimulation of acute-phase protein transcription (
      • Kishimoto T.
      • Taga T.
      • Akira S.
      Cytokine signal transduction.
      ). Much less is understood regarding the mechanism of the downregulation of transcription of negative acute-phase proteins during the APR, and many of the changes in lipid metabolism seen in infection and inflammation are mediated by decreases in proteins and their transcription (
      • Hardardóttir I.
      • Grunfeld C.
      • Feingold K.R.
      Effects of endotoxin on lipid metabolism.
      ).
      Nuclear hormone receptors are a large family of transcription factors, characterized by a central DNA binding domain that targets the receptor to specific DNA sequences (response elements) and a C-terminal portion that includes a ligand binding domain, which recognizes specific hormones, vitamins, drugs, or other lipophilic compounds (
      • Mangelsdorf D.J.
      • Evans R.M.
      The RXR heterodimers and orphan receptors.
      ,
      • Blumberg B.
      • Evans R.M.
      Orphan nuclear receptors—new ligands and new possibilities.
      ,
      • Kliewer S.A.
      • Lehmann J.M.
      • Willson T.M.
      Orphan nuclear receptors: shifting endocrinology into reverse.
      ,
      • Chawla A.
      • Repa J.J.
      • Evans R.M.
      • Mangelsdorf D.J.
      Nuclear receptors and lipid physiology: opening the X-files.
      ). Several nuclear hormone receptors, including the peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), and farnesoid X receptor (FXR), bind and are activated by lipids (
      • Blumberg B.
      • Evans R.M.
      Orphan nuclear receptors—new ligands and new possibilities.
      ,
      • Kliewer S.A.
      • Lehmann J.M.
      • Willson T.M.
      Orphan nuclear receptors: shifting endocrinology into reverse.
      ,
      • Chawla A.
      • Repa J.J.
      • Evans R.M.
      • Mangelsdorf D.J.
      Nuclear receptors and lipid physiology: opening the X-files.
      ,
      • Lee C.H.
      • Olson P.
      • Evans R.M.
      Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors.
      ,
      • Peet D.J.
      • Janowski B.A.
      • Mangelsdorf D.J.
      The LXRs: a new class of oxysterol receptors.
      ,
      • Edwards P.A.
      • Kast H.R.
      • Anisfeld A.M.
      BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis.
      ). Furthermore, the increased activity of these receptors regulates the transcription of a large number of genes involved in multiple aspects of lipid and lipoprotein metabolism (
      • Francis G.A.
      • Fayard E.
      • Picard F.
      • Auwerx J.
      Nuclear receptors and the control of metabolism.
      ). Because of their abilities to sense intracellular lipid levels and orchestrate changes in lipid metabolism, these nuclear hormone receptors have been recognized as liposensors (
      • Chawla A.
      • Repa J.J.
      • Evans R.M.
      • Mangelsdorf D.J.
      Nuclear receptors and lipid physiology: opening the X-files.
      ). Finally, these liposensors (PPARs, LXRs, and FXR) heterodimerize with retinoid X receptors (RXRs) for efficient gene regulation (
      • Mangelsdorf D.J.
      • Evans R.M.
      The RXR heterodimers and orphan receptors.
      ). As discussed in detail below, most of the genes of lipid metabolism that decrease during the APR are regulated by these liposensors and related transcription factors, and the downregulation of these liposensors plays a key role in those changes.

      Regulation of liposensors during infection and inflammation

      In hamsters and mice, LPS administration decreases both protein and mRNA levels of RXR-α, -β, and -γ in the liver (
      • Beigneux A.P.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      The acute phase response is associated with retinoid X receptor repression in rodent liver.
      ) (Table 4). The decrease in RXR occurs rapidly (within 4 h) and is sustained. Administering TNF and IL-1 reproduces these LPS effects. Similar reductions in RXR isoforms are seen in Hep3B cells treated with TNF and IL-1 but not IL-6, indicating that the decreases are directly induced by the cytokines (M-S. Kim, J. K. Shigenaga, A. H. Moser et al., unpublished observations). Furthermore, LPS administration also significantly reduces the hepatic nuclear DNA-binding activity of RXR homodimers to an RXR response element (
      • Beigneux A.P.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      The acute phase response is associated with retinoid X receptor repression in rodent liver.
      ).
      TABLE 4Changes in nuclear hormone receptors and their target genes involved in FA and TG metabolism during infection and inflammation
      TissueNuclear ReceptorTarget GenesFunction
      Adipocytes PPAR-γ ↓AP2 ↓Fatty acid transport (intracellular)
      LPL ↓TG catabolism
      FATP ↓Fatty acid transport
      CD36/FAT ↓Fatty acid and oxidized LDL uptake
      ACS ↓Fatty acid esterification
      Heart PPAR-α ↓LPL ↓TG catabolism
       PPAR-β/δ ↓FATP ↓Fatty acid transport
      CD36/FAT ↓Oxidized LDL uptake
      H-FABP ↓Fatty acid transport (intracellular)
      CPT-Iβ ↓Fatty acid oxidation
      ACS ↓Fatty acid esterification
      Skeletal muscle PPAR-α ?LPL ↓TG catabolism
       PPAR-β/δ ?FATP ↓Fatty acid transport
      CD36/FAT ↓Oxidized LDL uptake
      H-FABP ↓Fatty acid transport (intracellular)
      ACS ↓Fatty acid esterification
      Liver PPAR-α ↓FATP ↓Fatty acid transport
       PPAR-γ ↓CD36/FAT ↓Oxidized LDL uptake
      H-FABP ↓Fatty acid transport (intracellular)
      CPT-Iα ↓Fatty acid oxidation
       FXR ↓ApoC-II ↓Increases LPL activity
      ApoE ↓Lipoprotein metabolism
      ACS, acyl-CoA synthetase; AP2, adipocyte P2; CPT, carnitine palmitoyl transferase; FABP, fatty acid binding protein; FAT, fatty acid translocase; FATP, fatty acid transport protein; FXR, farnesoid X receptor; H-FABP, heart-FABP; PPAR, peroxisome proliferator-activated receptor; ↓, decreased levels of mRNA after LPS treatment.
      In addition to inhibiting the expression of the obligate liposensor heterodimer partner RXR, LPS and cytokine administration also reduces hepatic mRNA levels of PPAR-α and -γ, LXR-α, FXR, pregnane X receptor (PXR), and constitutive androstane receptor (CAR) (
      • Beigneux A.P.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      The acute phase response is associated with retinoid X receptor repression in rodent liver.
      ,
      • Kim M.S.
      • Shigenaga J.
      • Moser A.
      • Feingold K.
      • Grunfeld C.
      Repression of farnesoid X receptor during the acute phase response.
      ,
      • Beigneux A.P.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response.
      ). These decreases were associated with reductions in nuclear binding activity to a direct repeat-1 (DR-1) PPAR response element, a DR-4 LXR response element, and an inverted repeat-1 FXR response element (
      • Beigneux A.P.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      The acute phase response is associated with retinoid X receptor repression in rodent liver.
      ,
      • Kim M.S.
      • Shigenaga J.
      • Moser A.
      • Feingold K.
      • Grunfeld C.
      Repression of farnesoid X receptor during the acute phase response.
      ). In contrast, mRNA levels of PPAR-β/δ and LXR-β were not significantly altered in the liver after LPS treatment.
      In adipose tissue, PPAR-γ levels decrease after the administration of LPS or TNF (
      • Hill M.R.
      • Young M.D.
      • McCurdy C.M.
      • Gimble J.M.
      Decreased expression of murine PPARgamma in adipose tissue during endotoxemia.
      ) (Table 4). Treatment of adipocytes in vitro with TNF, IFN-γ, and IL-11 decreases mRNA levels of PPAR-γ (
      • Zhang B.
      • Berger J.
      • Hu E.
      • Szalkowski D.
      • White-Carrington S.
      • Spiegelman B.M.
      • Moller D.E.
      Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha.
      ,
      • Xing H.
      • Northrop J.P.
      • Grove J.R.
      • Kilpatrick K.E.
      • Su J.L.
      • Ringold G.M.
      TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARgamma without effects on Pref-1 expression.
      ,
      • Perrey S.
      • Ishibashi S.
      • Yahagi N.
      • Osuga J.
      • Tozawa R.
      • Yagyu H.
      • Ohashi K.
      • Gotoda T.
      • Harada K.
      • Chen Z.
      • Iizuka Y.
      • Shionoiri F.
      • Yamada N.
      Thiazolidinedione- and tumor necrosis factor alpha-induced downregulation of peroxisome proliferator-activated receptor gamma mRNA in differentiated 3T3-L1 adipocytes.
      ,
      • Waite K.J.
      • Floyd Z.E.
      • Arbour-Reily P.
      • Stephens J.M.
      Interferon-gamma-induced regulation of peroxisome proliferator-activated receptor gamma and STATs in adipocytes.
      ,
      • Meng L.
      • Zhou J.
      • Sasano H.
      • Suzuki T.
      • Zeitoun K.M.
      • Bulun S.E.
      Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma: mechanism of desmoplastic reaction.
      ). The effect of LPS and cytokines on RXR isoforms and other liposensors in adipose tissue remains to be determined. In cardiac muscle, our laboratory recently reported that LPS administration decreases RXR-α, -β, and -γ and PPAR-α and -β/δ expression (
      • Feingold K.
      • Kim M.S.
      • Shigenaga J.
      • Moser A.
      • Grunfeld C.
      Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response.
      ) (Table 4). To our knowledge, studies of the effect of inflammation and infection on the expression of RXR, PPAR, and other liposensors in skeletal muscle have not been carried out. Lastly, although the levels of liposensors are regulated in tissues that play a major role in the alterations of lipid metabolism during the APR, recent studies by our laboratory have shown that changes in the levels of RXR, PPARs, and LXRs were not found in the small intestine, an organ in which lipid metabolism is not significantly altered during infection and inflammation (
      • Khovidhunkit W.
      • Moser A.H.
      • Shigenaga J.K.
      • Grunfeld C.
      • Feingold K.R.
      Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR.
      ). Thus, liposensor levels specifically change in the tissues that exhibit changes in lipid metabolism during the APR.

      Consequences of decreased expression of liposensors

      Although it is likely that many factors influence the diverse changes in lipid and lipoprotein metabolism that occur in response to infection/inflammation, alterations in the activity of nuclear hormone receptor liposensors are likely to play a pivotal role in the coordinated regulation of FA and cholesterol metabolism that occurs during the APR, as can be seen by examining the effects on genes that liposensors are known to regulate.

      FA and TG metabolism

      As discussed earlier, infection/inflammation is characterized by an increase in lipolysis and a decrease in FA oxidation in adipose tissue, contributing to hypertriglyceridemia (
      • Feingold K.R.
      • Staprans I.
      • Memon R.A.
      • Moser A.H.
      • Shigenaga J.K.
      • Doerrler W.
      • Dinarello C.A.
      • Grunfeld C.
      Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
      ). PPAR-γ has been shown to directly regulate genes that promote the storage of fat in adipose tissue, including adipocyte P2, LPL, FATP, CD36/FAT, and ACS (
      • Lee C.H.
      • Olson P.
      • Evans R.M.
      Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors.
      ,
      • Fajas L.
      • Debril M.B.
      • Auwerx J.
      Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis.
      ,
      • Willson T.M.
      • Lambert M.H.
      • Kliewer S.A.
      Peroxisome proliferator-activated receptor gamma and metabolic disease.
      ). As discussed above, during infection and inflammation the expression of these genes is decreased, and it is likely that the reduction in PPAR-γ activity in adipose tissue contributes to the changes in these proteins that would reduce fat storage and enhance lipolysis.
      Likewise, downregulation of RXR-α, -β, and -γ and PPAR-α and -β/δ in cardiac muscle would be expected to reduce FA oxidation. Activation of PPAR-α and -β/δ induces the expression of many key enzymes required for FA oxidation, including LPL, FATP, CD36/FAT, heart-FABP (H-FABP), CPT-Iβ, and ACS (
      • Lee C.H.
      • Olson P.
      • Evans R.M.
      Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors.
      ,
      • Fruchart J.C.
      • Duriez P.
      • Staels B.
      Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis.
      ,
      • Wang Y.X.
      • Lee C.H.
      • Tiep S.
      • Yu R.T.
      • Ham J.
      • Kang H.
      • Evans R.M.
      Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity.
      ,
      • Lehman J.J.
      • Kelly D.P.
      Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth.
      ,
      • Schoonjans K.
      • Staels B.
      • Auwerx J.
      Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression.
      ). One can postulate that a reduction in PPAR-α and -β/δ activity in the heart during the APR contributes to the decreased expression of these genes (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Fuller J.
      • Grunfeld C.
      Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines.
      ,
      • Memon R.A.
      • Fuller J.
      • Moser A.H.
      • Smith P.J.
      • Feingold K.R.
      • Grunfeld C.
      In vivo regulation of acyl-CoA synthetase mRNA and activity by endotoxin and cytokines.
      ,
      • Memon R.A.
      • Bass N.M.
      • Moser A.H.
      • Fuller J.
      • Appel R.
      • Grunfeld C.
      • Feingold K.R.
      Down-regulation of liver and heart specific fatty acid binding proteins by endotoxin and cytokines in vivo.
      ,
      • Bagby G.J.
      • Spitzer J.A.
      Lipoprotein lipase activity in rat heart and adipose tissue during endotoxic shock.
      ) (Table 4). In skeletal muscle, there is also a decrease in FA oxidation, which is associated with a decrease in LPL, FATP, CD36/FAT, H-FABP, and ACS (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Fuller J.
      • Grunfeld C.
      Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines.
      ,
      • Memon R.A.
      • Fuller J.
      • Moser A.H.
      • Smith P.J.
      • Feingold K.R.
      • Grunfeld C.
      In vivo regulation of acyl-CoA synthetase mRNA and activity by endotoxin and cytokines.
      ,
      • Memon R.A.
      • Bass N.M.
      • Moser A.H.
      • Fuller J.
      • Appel R.
      • Grunfeld C.
      • Feingold K.R.
      Down-regulation of liver and heart specific fatty acid binding proteins by endotoxin and cytokines in vivo.
      ,
      • Bagby G.J.
      • Spitzer J.A.
      Decreased myocardial extracellular and muscle lipoprotein lipase activities in endotoxin-treated rats.
      ). Whether levels of RXR-α, -β, and -γ and PPAR-α and -β/δ change in skeletal muscle during the APR remains to be determined.
      Downregulation of RXR-α, -β, and -γ and PPAR-α and -γ in the liver during the APR could also reduce hepatic FA oxidation, as a number of key PPAR-regulated proteins required for FA oxidation are decreased, including FATP, CD36/FAT, liver-FABP, and CPT-Iα (ACS is decreased in mitochondria but not in endoplasmic reticulum) (
      • Memon R.A.
      • Feingold K.R.
      • Moser A.H.
      • Fuller J.
      • Grunfeld C.
      Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines.