JLR Commentaries
COVID-19: lipid disruption is pushing the envelope
A plethora of articles have been published on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and science has delivered, given the rapid development of vaccines and of novel antiviral therapeutics evaluated for their efficacy efficiently in platform trials. An unfolding story of interferon genetics and autoantibodies has begun to help us parse the reasons for varied susceptibility to severe disease and sequencing, and tracking at a global level has allowed for the rapid detection of new variants as they emerge.De(C1P)hering the role of ceramide-1-phosphate levels in skin wound healing
The skin is the largest organ of the body and serves several important roles: preventing water loss, serving as the first barrier against trauma—including UV radiation and chemicals—and pathogens, participating in metabolic functions such as vitamin D synthesis and temperature regulation, and informing the body of external conditions through billions of sensory and proprioceptor nerve cells. It is a dynamic organ composed of various cell types that have specific and unique functions, which are present in different skin layers, called the epidermis, dermis, and hypodermis.HDL, heart disease, and the lung
For more than 50 years, a low plasma level of HDL-cholesterol has been known as an independent risk factor of atherosclerotic cardiovascular diseases (ASCVD). In addition, HDL particles exert a plethora of potentially anti-atherogenic activities on many cells including endothelial cells, smooth muscle cells, as well as monocyte-derived macrophages and other inflammatory cells. Nevertheless, therapeutic interventions raising HDL-cholesterol did not improve the prevention of cardiovascular events beyond standard therapy with statins.A BOSSS platform: using functionalized lipids and click chemistry for new discoveries in lipid research
The development of new synthetic reporter lipids is critical in our continued pursuit to understand the intricacies of complex lipid physical and biological properties. Reporter functionalized lipids include, but are not limited to, fluorescently labeled lipids, electron paramagnetic probe-labeled lipids, and MRI lipids. Other functionalized lipids include those synthetic lipids (e.g., polyethylene glycolated lipids) used for drug delivery and gene transfection. Although these functionalized lipids are important reagents in the lipid biochemist's toolbox, the investigator must also consider that the employed functionalized lipid may not always necessarily mimic the natural lipid of interest.Understanding the underlying molecular pathways by which Mboat7/Lpiat1 depletion induces hepatic steatosis
Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease worldwide, paralleling the global epidemic of obesity and type 2 diabetes (1). In addition to the well-established metabolic and environmental risk factors, a body of evidence supports genetic predisposition as a pivotal driver of NAFLD development and progression to its life-threatening complications, namely cirrhosis and hepatocellular carcinoma. To date, several genetic loci have been identified contributing to NAFLD.Genetic evidence for independent causal relationships between metabolic biomarkers and risk of coronary artery diseases
Decades of epidemiological research have identified numerous risk factors and biomarkers that are associated with risk of coronary artery disease (CAD) and myocardial infarction. The most well recognized of these are circulating levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides, as well as metabolic syndrome-related traits, such as obesity, hypertension, and T2D (1). However, the association of a biomarker with CAD in observational studies does not necessarily prove a causal relationship.The bidirectional link between HDL and COVID-19 infections
It is well recognized that gram positive and negative bacterial infections, tuberculosis, fungal infections, and parasitic infections result in changes in plasma lipid levels (1–12). Of note, viral infections, such as HIV, Epstein-Barr virus, and Dengue fever, also similarly alter plasma lipid levels (13–15). Typically, infections decrease total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels with either elevated triglyceride or inappropriately normal triglyceride levels for the decreased nutritional status that characteristically occurs with infections.Long-lost friend is back in the game
Triglycerides (TGs) are transported in the bloodstream by TG-rich lipoproteins in the form of chylomicrons and VLDLs. The hydrolysis of circulating TGs is rate-limiting for their uptake into tissues and is catalyzed by the enzyme lipoprotein lipase (LPL) (1). The activity of LPL in different tissues is extensively regulated to be able to adjust to changes in lipid availability and demand. The regulation of LPL is mainly carried out at the posttranslational level and is mediated by two groups of proteins.A closer look at the mysterious HSD17B13
17-β hydroxysteroid dehydrogenase 13 (HSD17B13) belongs to a 15-member family that is involved in various metabolic processes, including steroid hormones, fatty acids, cholesterol, and bile acids (1). The human HSD17B13 gene is located on chromosome 4 (4q22.1), and its expression is highly restricted to the liver, specifically in hepatocytes but not other cell types in the liver (2, 3). The human HSD17B13 gene encodes a 300-amino-acid protein that is localized on lipid droplet (4). Interestingly, a few single-nucleotide polymorphisms (rs72613567, rs62305723, rs6834314, rs9992651, rs13118664, and rs4607179) of the human HSD17B13 gene have been linked to alcoholic and nonalcoholic fatty liver diseases by genome-wide association studies (5–12).Membrane domains beyond the reach of microscopy
The concept of lipid rafts describes the lateral compartmentalization of cellular membranes into domains of different compositions and physical properties (1). Raft themselves are relatively tightly packed domains enriched in sterols, sphingolipids, saturated lipids, and specialized raft-preferring membrane proteins (2). These patches in living cells are hypothesized to be nanoscopic and dynamic, serving key roles in biological processes including signal transduction, lipid and protein sorting, and viral entry during host cell infection.Commentary on SSO and other putative inhibitors of FA transport across membranes by CD36 disrupt intracellular metabolism, but do not affect fatty acid translocation
Long-chain fatty acid (LCFA) transport is fundamental to human pathophysiology, and its impairment has been implicated in cardiovascular disease, cancer, and obesity-linked diabetes (1–4). Physiologically, LCFAs are an energy source, precursors to regulatory molecules, and components of complex lipids such as triacylglycerols (TAGs), phospholipids, and cholesteryl esters, which occur in plasma lipoproteins and living cells. Most physiological LCFAs contain 16 or 18 carbons with up to three double bonds (5, 6) and associate with lipid surfaces at diffusion-controlled rates with kon ~109 M−1sec−1.HDL and pancreatic β cells: a SMO-king gun?
Levels of HDL cholesterol (HDL-C) are inversely correlated with risk of diabetes mellitus (1), and administration of reconstituted HDL to patients with diabetes mellitus enhances β-cell function (2). HDL protects β cells from apoptosis and inhibits the pro-apoptotic effects of LDL on islets (3). How HDL exerts these beneficial effects on β cell survival and function is unknown, but it has been hypothesized that these effects are mediated by ATP transporters, known to be critical for β-cell function (4, 5), or, alternatively, via an effect of HDL on the subcellular distribution of cholesterol and its metabolites and their interactions with various cellular receptors.Is CYP2C70 the key to new mouse models to understand bile acids in humans?
Humans and mice have substantially different bile acid (BA) pool compositions (1). As the major primary BAs, humans synthesize cholic acid (CA) and chenodeoxycholic acid (CDCA), whereas mice have mainly CA and 6-hydroxylated muricholic acids (MCAs) that are made from CDCA (Fig. 1). Hydroxylation at the C-6 position significantly affects the physicochemical properties of BAs, making the BA pool more hydrophilic, less potent as detergents, and less injurious. In addition, 6-hydroxylation dramatically changes BA signaling properties, converting the most potent endogenous FXR agonist (CDCA) to antagonists (MCAs).ANGPTL3, PCSK9, and statin therapy drive remarkable reductions in hyperlipidemia and atherosclerosis in a mouse model
The current focus of therapeutic intervention to reduce atherosclerotic cardiovascular disease (ACVD) risk is lowering plasma LDL-C to below 70 mg/dl using primarily statins. However, many patients on statins remain at high ASCVD risk (1). Monoclonal antibodies against PCSK9, in addition to statins, can further reduce LDL-C. Also, Mendelian randomization reports show that moderately elevated triglyceride-rich lipoproteins and remnant cholesterol increase ASCVD risk independently of LDL-C levels (2).Worming our way toward multiple evolutionary origins of convergent sterol pathways
Sterols represent one of the most ubiquitous and diverse classes of biological molecules derived from the common precursor, mevalonic acid. While there are thematically similar modes by which various organisms synthesize sterols, there also are some unique twists in the pathways by which such organisms produce sterols as well as differences in the chemical nature of the dominant resident sterol present at steady-state in a given organism or cell type. In this issue of the Journal of Lipid Research, David Nes and colleagues [Zhou et al.α-Galactosylceramide: a potent immunomodulator produced by gut microbes
Intestinal bacteria have coevolved with humans to respond to and regulate metabolism in a species-specific manner. This commensalism, in turn, influences local and systemic energy homeostasis and immune regulation. Although recent advances in high-throughput technologies have enabled researchers to connect these unique genetic and metabolic microbial signatures with human health and disease, gaps remain in our understanding of the specific mechanisms by which intestinal bacteria impact complex human biology.A wolf in sheep's clothing: unmasking the lanosterol-induced degradation of HMG-CoA reductase
The conversion of the two-carbon acetyl-CoA to the twenty-seven-carbon, tetracyclic cholesterol via the mevalonate pathway is a remarkable feat of anabolic engineering. Its earliest steps yield mevalonate, followed by isoprenoid precursors that condense to produce the squalene backbone of cholesterol (Fig. 1). Oxygenation and cyclization form the steroid nucleus, upon which the pathway bifurcates into two parallel branches, Bloch and Kandutsch-Russell, each involving successive rounds of reduction and demethylation.Life is complicated: so is apoCIII
Apolipoprotein (apo)CIII, comprised of 79 amino acids and with a mass of 8.8 kDa, was first isolated and characterized 50 years ago by Brown et al. (1). Studies conducted during the following decade demonstrated that apoCIII was an inhibitor of both LPL (2) and the uptake of triglyceride-rich lipoproteins (TGRLs) and remnants by perfused livers (3, 4). Lipoprotein kinetic studies of two sisters with complete absence of apoCIII (5) demonstrated, in vivo, that absence of this protein resulted in a dramatic increase in lipolysis of VLDL-TG (6).Building bridges: PCSK7 as a NAFLD candidate gene connecting hepatic inflammation with hypertriglyceridemia
Nonalcoholic fatty liver disease (NAFLD) now ranks as the most prevalent liver disease worldwide (1), but progression from its more indolent stage of nonalcoholic fatty liver (NAFL) to advanced stages of nonalcoholic steatohepatitis (NASH) is not well understood. The accumulation of neutral lipids (principally triglycerides, TGs) within hepatocellular lipid droplets (LDs) in obese subjects with NAFL largely reflects increased de novo lipogenesis. In addition, the excessive hepatic TG burden also promotes augmented VLDL secretion and leads to systemic hypertriglyceridemia.Anti-parasitic drug discovery takes a giant leap forward
Although rare, parasitic infections can be severe and cause death. Presently, there is a paucity of compounds to treat these infections. Zhou et al. (1) have identified two steroidal suicide substrate inhibitors [cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT)] directly inhibiting the sterol methyltransferase activities of Acanthamoeba castellanii (AcSMTs), the organism causing blinding keratitis (BK) and granulomatous amebic encephalitis (GAE). They demonstrated that these steroids 1) covalently bound and inhibited sterol C28-methyltransferase (Ac28-SMT), 2) were highly growth inhibitory to trophozoite growth (IC50~nM), and 3) were nontoxic to mammalian cells.Intramuscular adipocytes: a buried adipose tissue depot deserving more exploration
Adipocytes in the skeletal muscle are cellular populations that directly communicate nutrient stores to muscle and regulate glucose homeostasis (1). There are multiple depots of adipocytes in skeletal muscle, including intermuscular adipocytes found in the space between muscle groups, and intramuscular adipocytes, which are located between muscle fibers. The intramuscular adipocyte population is becoming an area of research focus because it is an important measure of meat quality for the livestock industry and is associated with adverse human health conditions, including obesity and sarcopenia (2).Regulation of lipophagy in NAFLD by cellular metabolism and CD36
Nonalcoholic fatty liver disease (NAFLD) progresses in a subset of patients to nonalcoholic steatohepatitis (NASH) with inflammation, fibrosis, and increased risk of hepatocellular carcinoma (1). A better understanding of the factors involved in the development, progression, or resolution of hepatic steatosis and NAFLD will expand the repertoire of tools available for treatment of NASH and its associated comorbidities.Beyond fat accumulation, NAFLD genetics converges on lipid droplet biology
Nonalcoholic fatty liver disease (NAFLD) is epidemiologically associated with obesity, insulin resistance, and dyslipidemia, and is rapidly becoming the leading cause of liver disease. The presence of NAFLD is associated with an increased risk of cardiovascular events and neoplastic diseases, cirrhosis, and hepatocellular carcinoma. However, there is a huge interindividual variability in the susceptibility to develop liver-related complications, which is partly accounted for by genetic predisposition (1).The ceramide ratio: a predictor of cardiometabolic risk
Circulating lipids drive the tissue dysfunction that underlies cardiovascular disease and diabetes. Clinical indices of risk of these metabolic disorders include serum levels of LDLs, total and LDL-cholesterol, and triglycerides, all of which reveal heightened susceptibility for major adverse cardiac events (MACEs). Despite their widespread use, these established clinical biomarkers only weakly forecast cardiovascular outcomes, leaving substantial need to develop more reliably predictive diagnostic tests.Hepatic thyroid hormone receptor β1 agonism: good for lipids, good for bile?
Hepatic bile formation plays an essential role in lipid digestion and absorption, cholesterol homeostasis, and excretion of lipid soluble metabolites and xenobiotics. Bile is a complex, lipid-rich micellar solution composed primarily of water, inorganic solutes, and organic solutes such as amphipathic conjugated bile acids (BAs), the membrane phospholipid phosphatidylcholine (PC), cholesterol, bile pigments, and endogenous metabolites (1). The major organic solutes, BAs, phospholipids, and cholesterol are termed “biliary lipids” and their secretion into bile is mediated by three distinct canalicular membrane ABC transporters, ABCB11(BSEP), ABCB4 (MDR3) (Abcb4/Mdr2 in rodents), and ABCG5/ABCG8, respectively (1).The unmasking of the lipid binding face of sphingosine kinase 1
Sphingosine-1-phosphate (S1P) is a pro-inflammatory lipid and pro-survival signal generated primarily by phosphorylation of sphingosine via sphingosine kinase 1 (SK1). SK1 is an ~43 kDa enzyme with two domains and an active site within a cleft between the two domains (1). Although the role of SK1 in generating S1P and activating downstream targets is fairly well studied, there has been a paucity of information on how SK1 interacts with lipid membranes/cell membranes where it presumably accesses its substrate, sphingosine.In search of a physiological function of lipoprotein(a): causality of elevated Lp(a) levels and reduced incidence of type 2 diabetes
“Shallow (wo)men believe in luck or in circumstance. Strong (wo)men believe in cause and effect.”(Ralph Waldo Emerson, The Conduct of Life, 1860).AIBP, inflammation, and atherosclerosis
Atherosclerosis (AS), a major etiology of cardiovascular disease, is considered to be a chronic inflammatory disease characterized by excessive inflammatory cells, such as macrophages, accumulated in the arterial wall (1). As the main effector cells of the immune/inflammatory system, macrophages engulf lipids and produce various inflammatory factors, thus participating in the progress of AS (1–3). Therefore, it is very important to clarify the mechanisms that regulate macrophage-related inflammatory response for the prevention of AS.The good side of cholesterol: a requirement for maintenance of intestinal integrity
The relationship between high plasma cholesterol levels and cardiovascular disease is well established and has led to development of cholesterol-lowering strategies that dramatically reduce the rate of cardiovascular mortality and morbidity in the general population. Although these major advances have garnered well-deserved recognition in the popular press, unfortunately, the word ‘cholesterol’ has also gained considerable negative connotations in society. It is important to note that cholesterol is essential for mammalian cell growth and survival, as evidenced from a study reported in this issue of the Journal of Lipid Research.Lipoprotein(a): the common, likely causal, yet elusive risk factor for cardiovascular disease
Lipoprotein(a) [Lp(a)], first described in 1963 by the Norwegian Kaare Berg, consists of a low density lipoprotein (LDL)-like particle with an additional apolipoprotein covalently bound to apolipoprotein B; apolipoprotein(a) [apo(a)] (1). Lp(a) plasma concentrations are highly heritable with >50% of the variation in levels attributable to genetic variation in the LPA gene locus coding for apo(a) synthesized by hepatocytes. Of particular importance is the so-called kringle-IV type 2 (KIV-2) LPA copy number variant (CNV) determining the number of kringle-shaped protein structures in apo(a), thus determining apo(a) isoform size, which correlates inversely with plasma Lp(a) levels (1).Anti-inflammatory liaisons: T regulatory cells and HDL
The report in this issue of the Journal of Lipid Research by Rueda et al. shows that the survival and viability of Tregs is improved by incubation with HDL. Previous research over the last 20 years had demonstrated that plasma HDL possessed anti-inflammatory properties (1–4). Much of the early work focused on HDL as a vehicle to carry oxidized lipid products to the liver for catabolism as well as to inhibit the oxidation of LDL. Because HDL was proposed to carry oxidized lipids for excretion, it was also suggested that HDL could go “bad,” or become pro-inflammatory if it was overloaded with oxidized products or if the particles were not removed by catabolism.Anacetrapib-driven triglyceride lowering explained: the fortuitous role of CETP in the intravascular catabolism of triglyceride-rich lipoproteins
Atherosclerosis and associated CVD remains the largest cause of mortality worldwide (1). Despite substantial benefit offered by statin monotherapy, cardiovascular events still claim more lives than any other cause. To address this unmet therapeutic need, drug discovery efforts have shifted toward novel approaches to alter cholesterol metabolism that do not rely on inhibition of cholesterol synthesis. Elevation of HDL cholesterol has been a popular therapeutic strategy (2). However, recent clinical trials (3,4) have failed to show clinical benefits of HDL cholesterol elevation, and Mendelian randomization studies question the causal link between HDL cholesterol levels and CVD (5).Will the real bile acid sulfotransferase please stand up? Identification of Sult2a8 as a major hepatic bile acid sulfonating enzyme in mice
This year marks the 50th anniversary of the publication by Robert Palmer (1, 2) recognizing the formation of bile acid sulfates as a mechanism for bile acid elimination in humans. Like steroids, bile acids undergo sulfonation in liver and other tissues [reviewed by Alnouti in (3)]. This important phase II detoxification reaction transfers a sulfonate group (SO3−) from the universal donor, 3′-phosphoadenosine 5′-phosphosulfate (PAPS), to a hydroxyl, amine, or carboxylic acid group of a substrate.Directing eicosanoid esterification into phospholipids
Eicosanoids are well known potent signaling mediators generated by cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (CYP) enzymes in immune cells, platelets, and inflammatory activated tissues. As free acids, they signal by binding to G protein-coupled receptors following secretion from their cell of origin. For many years, it has been known that when added to cells, exogenous eicosanoids can be incorporated into more complex lipids, including phospholipids (PLs). However until recently this was considered little more than an epiphenomenon.Acyl-CoA wax alcohol acyltransferase 2: its regulation and actions in support of color vision
The enzyme acyl-CoA wax alcohol acyltransferase 2 (AWAT2), which is also commonly referred to as multifunctional O-acyltransferase (MFAT), was first identified more than a decade ago by several groups as an enzyme responsible for wax monoester biosynthesis in the skin (1–3). These early investigations established that AWAT2 is highly expressed in both human and rodent skin, primarily in mature sebocytes of the sebaceous gland (4). Although AWAT2 was reported to be expressed predominantly in skin, low levels of expression were also reported for human testis, lung, brain, and adipose tissue suggesting a broad role of this enzyme in the body (3).Understanding mouse bile acid formation: Is it time to unwind why mice and rats make unique bile acids?
Current knowledge on bile acid metabolism is largely based on extrapolations from animal experiments where the mouse has taken a front position, greatly due to the development of techniques making it feasible to construct mouse models where specific functions are deficient or overexpressed. However, there are several major differences between mice and humans as regards bile acid metabolism that are important to recognize when interpreting data obtained from experiments on mice and extrapolating that data to humans.Multidimensional regulation of lipoprotein lipase: impact on biochemical and cardiovascular phenotypes
LPL contributes profoundly to physiologic lipoprotein metabolism and to tissue-specific substrate delivery and utilization (1). Perturbed LPL activity affects global energy balance, insulin action, body weight maintenance, and CVD risk; the latter alluded to by contemporary human genetic studies. LPL is the pivotal rate-limiting mediator of hydrolysis of core TGs from TG-rich lipoproteins, particularly chylomicrons and VLDL (2, 3). The products of LPL-mediated catalysis, such as fatty acids and monoacylglycerol, are handled differentially at local sites depending on the global hormonal and nutritional milieu, and local energy needs.EPA and/or DHA? A test question on the principles and opportunities in utilizing the therapeutic potential of omega-3 fatty acids
Decades of research and certainly more than 20,000 papers have been dedicated to the health benefits of omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs). We have learned that n-3 LC-PUFAs modulate multiple molecular processes and exert pleiotropic beneficial effects that, depending on the pathophysiological context, may range from anti-inflammation and triglyceride-lowering to cardioprotection and anti-arrhythmia, or even improved cognitive function (1, 2). However, a challenging question remains about how molecular events translate into physiological responses and finally to desired health benefits.New mechanisms by which statins lower plasma cholesterol
The use of an enzyme inhibitor in vivo to lower a metabolic rate often results in the activation of the targeted enzymatic reaction. The dose of inhibitor is adjusted so that the desired effect is achieved and maintained in spite of the activation of the enzyme. After statins were developed in the 1970s to inhibit HMG-CoA reductase and lower plasma cholesterol, it was soon reported that these drugs induce a strong activation of the reductase (1). This was not a particular concern to clinicians because, in many patients, the dose of statin could be adjusted to keep the plasma concentration of cholesterol in a range that decreased the risk of myocardial infarction.Lipid signaling in keratinocytes: Lipin-1 plays a PArt
Although it is well recognized that lipids play an important role in providing the structural barriers that delineate the cell and its various organelles, accumulating evidence also points to the critical involvement of lipids in cell signaling. Unlike some signaling molecules, however, an understanding of lipids as signals must take into account the additional intricacy afforded by the fact that many lipid signals can be interconverted. For example, diacylglycerol (DAG), a lipid known to activate enzymes such as protein kinases and guanine nucleotide exchange factors, can be phosphorylated by diacylglycerol kinase to yield phosphatidic acid (PA), which has its own effector enzymes (Fig.Srebp2: A master regulator of sterol and fatty acid synthesis
Sterol regulatory element-binding proteins (SREBPs, including SREBP1a, SREBP1c, and SREBP2) are basic-helix-loop-helix leucine zipper (bHLH-Zip) transcription factors that regulate the synthesis and cellular uptake of two major building blocks of cell membranes: cholesterol and fatty acids. For cholesterol biosynthesis, SREBPs activate expression of genes such as HMG-CoA reductase (HMGCR), HMG-CoA synthase (HMGCS), and mevalonate kinase (MVK). For cholesterol uptake, SREBPs activate expression of the LDL receptor (LDLR).Extracellular vesicles and ceramide: new mediators for macrophage chemotaxis?
Intercellular communication is a vital process in the function of all multicellular organisms. Communication between liver cells is known to occur through multiple pathways including secreted mediators, direct cell-cell contact, and by membrane-surrounded particles referred (variably) to as extracellular vesicles (EVs) or exosomes. Although the term exosome was initially reserved to describe vesicles that were released after the fusion of the multivesicular endosomes with the plasma membrane, it is likely that circulating EVs represent a heterogenous population of exosomes, microparticles, or microvesicles in a size range of 40–100nm, yet which are difficult to resolve using current purification methods (1).Kinetic modeling and the rise of systems pharmacology
The paper by Gadkar, Lu, and colleagues in this issue of the Journal of Lipid Research offers an opportunity to comment on the intersection of two different philosophies in kinetic modeling that are just beginning to join forces in the practical worlds of disease modeling and systems pharmacology. First, some background.Reduction in PCSK9 levels induced by anacetrapib: an off-target effect?
Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) and cholesteryl ester transfer protein (CETP) are both under current investigation as agents with the potential to reduce atherosclerotic cardiovascular disease (ASCVD) risk. Inhibitors of PCSK9 reduce the concentration of LDL cholesterol by more than 60%, while inhibitors of CETP reduce LDL cholesterol by up to 45% and increase HDL cholesterol by up to 180%.Specialized pro-resolving mediators: do they circulate in plasma?
This issue of the Journal of Lipid Research reports a patient-oriented study by workers at the University of Pennsylvania (Penn group) (1) using n-3 PUFA ester supplementation in attempts to detect the appearance of oxidized DHA and EPA in plasma and urine. Fish oil and purified n-3 PUFA supplementations have certainly emerged on the conscious level of the Western consumer by intense advertising, both for prescription supplements (e.g., Lovaza fish oil) and over-the-counter fish oil products and related biological extracts.Scap and the intestinal epithelial stem cell niche: new insights from lipid biology
SCAP is required for proteolytic cleavage and activation of sterol regulatory element-binding proteins (SREBPs). Once activated, SREBPs translocate to the nucleus to initiate transcription of genes required for fatty acid and sterol synthesis. Liver specific Scap deletion protects mice from fatty liver and carbohydrate-induced hypertriglyceridemia (1). As such, SCAP inhibition is a potential therapeutic target for disorders linked to hyperlipidemia and hepatic steatosis. Both statins and ezetimibe increase the abundance of nuclear SREBP and provoke a compensatory increase in intestinal cholesterol synthesis.SAA: a link between cholesterol efflux capacity and inflammation?
Serum amyloid A (SAA) concentration in plasma increases markedly following inflammation or infection, with the liver being the principal site of its synthesis. SAA was first reported to be associated with both human and animal HDLs in the late 1970s (1), but is also associated with other lipoprotein fractions (2, 3). Further studies showed that HDL particles isolated from endotoxin-treated mice contain up to two SAAs per apoA-I molecule (4). When SAA containing HDL was reinjected into mice it was cleared from the plasma more rapidly than apoA-I (5–8).HDL-C, ABCA1-mediated cholesterol efflux, and lipoprotein(a): insights into a potential novel physiologic role of lipoprotein(a)
Lipoprotein(a) [Lp(a)], an atherogenic lipoprotein consisting of apo(a) covalently bound to apo B-100 of LDL, is a prevalent genetic risk factor for cardiovascular disease. Several genome wide association studies have established an association between SNPs in LPA, the gene encoding apo(a), and coronary artery disease and myocardial infarction (MI) (1–3). Moreover, recent Mendelian randomization studies also demonstrate that LPA SNPs associated with elevated plasma Lp(a) levels also predict development of MI (4, 5) and aortic valve stenosis (6, 7), supporting a role for Lp(a) as a genetically determined, independent, causal risk factor for these diseases.
