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).
