JLR Commentaries
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.
