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Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host1
Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
Department of Medicine, University of California, San Francisco, and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, CA
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 (
). 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) (
). 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 (
). 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 (
). 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) (
). 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 (
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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
Hypertriglyceridemia and its relation to tissue lipoprotein lipase activity in endotoxemic, Escherichia coli bacteremic, and polymicrobial septic rats.
Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.
Modifications of plasma lipids, lipoproteins and apolipoproteins in advanced cancer patients treated with recombinant interleukin-2 and autologous lymphokine-activated killer cells.
Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
). 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 (
Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
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) (
Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.
Modifications of plasma lipids, lipoproteins and apolipoproteins in advanced cancer patients treated with recombinant interleukin-2 and autologous lymphokine-activated killer cells.
). 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 (
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.
). 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 (
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 (
Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
Evidence for two classes of cytokines that stimulate hepatic lipogenesis: relationships among tumor necrosis factor, interleukin-1 and interferon-alpha.
), 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 (
). The time course for stimulation of hepatic FA synthesis and VLDL secretion is consistent with the time course for TNF-induced hypertriglyceridemia (
). 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 (
) (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 (
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 (
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 (
). 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.
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.
). 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 (
Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
). 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 (
). 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) (
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 (
), 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) (
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 (
Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP.
). 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 (
). 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 (
). 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 (
) (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 (
). 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 (
), 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 (
) (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 (
). 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 (
). 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 (
). 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 (
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 (
). 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 (
Recombinant human interleukin-1 suppresses lipoprotein lipase activity, but not expression of lipoprotein lipase mRNA in mesenchymal rat heart cell cultures.
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.
). 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 (
). 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 (
). 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 (
). 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 (
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.
), 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 (
Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
). Because apoE is required for the clearance of TG-rich lipoproteins, decreased apoE could contribute to the delayed clearance observed in rats with infection (
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 (
) (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 (
). 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 (
). 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 (
) (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 (
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 (
), 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 (
). 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 (
). 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 (
Modifications of plasma lipids, lipoproteins and apolipoproteins in advanced cancer patients treated with recombinant interleukin-2 and autologous lymphokine-activated killer cells.
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
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 (
). 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 (
) (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 (
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 (
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.
). 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 (
). 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) (
). 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 (
). 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 (
). 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) (
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.
Decreased cholesteryl ester transfer protein (CETP) mRNA and protein and increased high density lipoprotein following lipopolysaccharide administration in human CETP transgenic mice.
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.
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.
). 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 (
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 (
High-density lipoprotein has different binding capacity for different apoproteins. The amyloidogenic apoproteins are easier to displace from high-density lipoprotein.
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 (
). 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 (
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 (
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 (
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.
). 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 (
). 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 (
). 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.
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 (
), 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 (
). 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 (
) (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 (
). 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 (
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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
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 (
). 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 (
). 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 (
). Because of their abilities to sense intracellular lipid levels and orchestrate changes in lipid metabolism, these nuclear hormone receptors have been recognized as liposensors (
). 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 (
) (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 (
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) (
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 (
Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha.
TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARgamma without effects on Pref-1 expression.
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 (
) (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 (
). 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 (
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 (
). 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 (
) (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 (
). 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) (
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