The scavenger receptor, class B type 1 (SR-B1), is a multiligand membrane receptor protein that functions as a physiologically relevant high-density lipoprotein (HDL) receptor whose primary role is to mediate selective uptake or influx of HDL-derived cholesteryl esters into cells and tissues. SR-B1 also facilitates the efflux of cholesterol from peripheral tissues, including macrophages, back to liver. As a regulator of plasma membrane cholesterol content, SR-B1 promotes the uptake of lipid soluble vitamins as well as viral entry into host cells. These collective functions of SR-B1 ultimately affect programmed cell death, female fertility, platelet function, vasculature inflammation, and diet-induced atherosclerosis and myocardial infarction. SR-B1 has also been identified as a potential marker for cancer diagnosis and prognosis. Finally, the SR-B1-linked selective HDL-cholesteryl ester uptake pathway is now being evaluated as a gateway for the delivery of therapeutic and diagnostic agents. In this review, we focus on the regulation and functional significance of SR-B1 in mediating cholesterol movement into and out of cells.

-ichi Osuga, Shun Ishibashi, and Fredric B. Kraemer. Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice. Am J Physiol Endocrinol Metab 285: E1182-E1195, 2003. First published September 3, 2003 10.1152/ajpendo.00259.2003.-To elucidate the role of hormone-sensitive lipase (HSL) in diet-induced obesity, HSLdeficient (HSL Ϫ/Ϫ ) and wild-type mice were fed normal chow or high-fat diets. HSL Ϫ/Ϫ mice were resistant to diet-induced obesity showing higher core body temperatures. Weight and triacylglycerol contents were decreased in white adipose tissue (WAT) but increased in both brown adipose tissue (BAT) and liver of HSL Ϫ/Ϫ mice. Serum insulin levels in the fed state and tumor necrosis factor-␣ mRNA levels in adipose tissues were higher, whereas serum levels of adipocyte complement-related protein of 30 kDa (ACRP30)/adiponectin and leptin, as well as mRNA levels of ACRP30/adiponectin, leptin, resistin, and adipsin in WAT, were lower in HSL Ϫ/Ϫ mice than in controls. Expression of transcription factors associated with adipogenesis (peroxisome proliferator-activated receptor-␥, CAAT/enhancer-binding protein-␣) and lipogenesis (carbohydrate response element-binding protein, adipocyte determination-and differentiation-dependent factor-1/sterol regulatory element-binding protein-1c), as well as of adipose differentiation markers (adipocyte lipid-binding protein, perilipin, lipoprotein lipase), lipogenic enzymes (glycerol-3-phosphate acyltransferase, acyl-CoA:diacylglycerol acyltransferase-1 and -2, fatty acid synthase, ATP citrate lyase) and insulin signaling proteins (insulin receptor, insulin receptor substrate-1, GLUT4), was suppressed in WAT but not in BAT of HSL Ϫ/Ϫ mice. In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL Ϫ/Ϫ mice. Our results suggest that impaired lipolysis in HSL deficiency affects lipid metabolism through alterations of adipose differentiation and adipose-derived hormone levels. adipocyte; differentiation; insulin; leptin; fatty liver HORMONE-SENSITIVE LIPASE (HSL) mediates the cytosolic hydrolysis of triacylglycerols (lipolysis) and cholesteryl esters (12). HSL is expressed in various tissues, including white (WAT) and brown adipose tissues (BAT), cardiomyocytes, adrenocortical cells, and gonads (11). Because HSL is responsible for the release of free fatty acids (FFA) from stored triacylglycerols in adipose tissues, the enzyme has been proposed to play an essential role in the regulation of body weight and fat mass. We previously reported, however, that the body weight of HSL-deficient (HSL Ϫ/Ϫ ) mice generated by homologous recombination fed a normal chow diet did not differ from that of wild-type (HSL ϩ/ϩ ) mice despite the presence of a markedly suppressed hydrolysis of triacylglycerols and cholester...

The PPARs are a subfamily of three ligand-inducible transcription factors, which belong to the superfamily of nuclear hormone receptors. In mammals, the PPAR subfamily consists of three members: PPAR-α, PPAR-β/δ and PPAR-γ. PPARs control the expression of a large number of genes involved in metabolic homeostasis, lipid, glucose and energy metabolism, adipogenesis and inflammation. PPARs regulate a large number of metabolic pathways that are implicated in the pathogenesis of metabolic diseases such as metabolic syndrome, Type 2 diabetes mellitus, nonalcoholic fatty liver disease and cardiovascular disease. The aim of this review is to provide up-to-date information about the biochemical and metabolic actions of PPAR-β/δ and PPAR-γ, the therapeutic potential of their agonists currently under clinical development and the cardiovascular disease outcome of clinical trials of PPAR-γ agonists, pioglitazone and rosiglitazone.

This article provides a comprehensive review about the molecular and metabolic actions of PPAR-α. It describes its structural features, ligand specificity, gene transcription mechanisms, functional characteristics and target genes. In addition, recent progress with the use of loss of function and gain of function mouse models in the discovery of diverse biological functions of PPAR-α, particularly in the vascular system and the status of the development of new single, dual, pan and partial PPAR agonists (PPAR modulators) in the clinical management of metabolic diseases are presented. This review also summarizes the clinical outcomes from a large number of clinical trials aimed at evaluating the atheroprotective actions of current clinically used PPAR-α agonists, fibrates and statin-fibrate combination therapy.

Programmed cell death (PCD) is a critical biological process involved in many important processes, and defects in PCD have been linked with numerous human diseases. In recent years, the protein architecture in different PCD subroutines has been explored, but our understanding of the global network organization of the noncoding RNA (ncRNA)-mediated cell death system is limited and ambiguous. Hence, we developed the comprehensive bioinformatics resource (ncRDeathDB, www.rna-society.org/ncrdeathdb ) to archive ncRNA-associated cell death interactions. The current version of ncRDeathDB documents a total of more than 4600 ncRNA-mediated PCD entries in 12 species. ncRDeathDB provides a user-friendly interface to query, browse and manipulate these ncRNA-associated cell death interactions. Furthermore, this resource will help to visualize and navigate current knowledge of the noncoding RNA component of cell death and autophagy, to uncover the generic organizing principles of ncRNA-associated cell death systems, and to generate valuable biological hypotheses.

Chemerin is a chemoattractant involved in immunity as well as an adipokine, whose activity is regulated by successive proteolytic cleavages at its C-terminus. Chemerin’s C-terminal sequence and its proteolytic cleavage sites are highly conserved between human and mouse, as well as in other species. We produced, purified and characterized different mouse chemerin forms. Ca2+ mobilization assay showed that the EC50 values for mchem161T and mchem157R were 135.8 ± 158 nM and 71.2 ± 55.4 nM, respectively, whereas mchem156S and mchem155F had a 20-fold higher potency with an EC50 of 4.6 ± 1.8 nM and 3.6 ± 3.0 nM, respectively, likely representing the two physiologically active forms of chemerin. No agonist activity was found for mchem154A. Similar results were obtained in a chemotaxis assay. To identify and quantify the in vivo mouse chemerin forms in biological samples, we developed specific ELISAs for mchem162K, mchem157R, mchem156S, mchem155F and mchem154A, using antibodies raised against peptides from the C-terminus of the different mouse chemerin forms. The prochemerin form, mchem162K, was the major chemerin form in plasma with its increase matching the increase of total plasma chemerin in obese mice. During the onset of obesity in high-fat diet fed mice, mchem156S was elevated in plasma. In contrast, mchem155F was the dominant form in epididymal fat extracts. Our study provides the first direct evidence that mouse chemerin undergoes extensive, dynamic and tissue-specific proteolytic processing in vivo, similar to human chemerin, underlining the importance of measuring individual chemerin forms in studies of chemerin biology in mouse models.

Hormone-sensitive lipase (HSL) hydrolyzes triglyceride (TG) in adipose tissue. HSL is also expressed in heart. To explore the actions of cardiac HSL, heart-specific, tetracycline (Tc)-controlled HSL-overexpressing mice were generated. Tc-responsive element-HSL transgenic (Tg) mice were generated and crossed with myosin heavy chain (MHC)alpha-tTA Tg mice, which express the Tc-responsive transactivator (tTA) in the heart. The double-Tg mice (MHC-HSL) were maintained with doxycycline (Dox) to suppress Tg HSL. Upon removal of Dox, cardiac HSL activity and protein increased 12- and 8-fold, respectively, and the expression was heart specific. Although cardiac TG content increased twofold in control mice after an overnight fast, it did not increase in HSL-induced mice. Electron microscopy showed numerous lipid droplets in the myocardium of fasted control mice, whereas fasted HSL-induced mice showed virtually no droplets. Microarray analysis showed altered expression of cardiac genes for fatty acid oxidation, transcription factors, signaling molecules, cytoskeletal proteins, and histocompatibility antigens in HSL-induced mice. Thus cardiac HSL plays a role in controlling accumulation of triglyceride droplets and can affect the expression of a number of cardiac genes.

Objective During the coronavirus disease 2019 (COVID-19) pandemic, exploring insulin resistance and β-cell activity is important for understanding COVID-19-associated new-onset diabetes. This study aimed to assess insulin sensitivity and fasting insulin secretion in COVID-19 patients without diabetes on admission and at 3 and 6 months after discharge. Methods This 6-month prospective study assessed data from the records of 64 patients without diabetes diagnosed with COVID-19 at Wenzhou Central Hospital, China. Each patient was followed up for 3 and 6 months after discharge. Repeated measures analysis of variance was used to investigate differences in multiple measurements of the same variable at different times. Linear regression analysis was performed to analyze the contributor for changes in triglyceride-glucose (TyG) index. Results Fasting C-peptide levels in patients at baseline were lower than the normal range (1.1-4.4 μg/L). Compared with baseline, patients had significantly elevated fasting C-peptide levels (0.35±0.24 vs. 2.36±0.98 vs. 2.52±1.11 μg/L, P ˂0.001), HOMA-CP (0.42, IQR 0.36–0.62 vs. 2.54, IQR 1.95-3.42 vs. 2.90, IQR 2.02-4.23, P ˂0.001) and TyG indexes (8.57±0.47 vs. 8.73±0.60 vs. 8.82±0.62, P =0.006), and decreased fasting glucose levels (5.84±1.21 vs. 4.95±0.76 vs. 5.40±0.68 mmol/L, P =0.003) during the 3 and 6-month follow-up. Male gender [β (95%CI): -0.312 (-0.590, -0.034)], age [0.012 (0.001, 0.023)], interferon-alfa treatment during hospitalization [0.540 (0.029, 1.051)], and changes in TC [0.217 (0.069, 0.366)] and HDL [-0.477 (-0.881, -0.074)] levels were significantly associated with changes in the TyG index. Conclusions Our study provided the first evidence that COVID-19 may increase the risk of insulin resistance in patients without diabetes.