JLR Commentaries
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).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.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 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).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.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).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.
