Intramuscular adipocytes: a buried adipose tissue depot deserving more explorationAdipocytes 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 CD36Nonalcoholic 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.
The ceramide ratio: a predictor of cardiometabolic riskCirculating 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).
AIBP, inflammation, and atherosclerosisAtherosclerosis (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 integrityThe 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 diseaseLipoprotein(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 HDLThe 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 lipoproteinsAtherosclerosis 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 miceThis 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 phospholipidsEicosanoids 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.
New mechanisms by which statins lower plasma cholesterolThe 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.
Kinetic modeling and the rise of systems pharmacologyThe 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.