CD36 (cluster of differentiation 36) is a scavenger receptor that functions in high-affinity tissue uptake of long-chain fatty acids (FAs) and contributes under excessive fat supply to lipid ...accumulation and metabolic dysfunction. This review describes recent evidence regarding the CD36 FA binding site and a potential mechanism for FA transfer. It also presents the view that CD36 and FA signaling coordinate fat utilization, a view that is based on newly identified CD36 actions that involve oral fat perception, intestinal fat absorption, secretion of the peptides cholecystokinin and secretin, regulation of hepatic lipoprotein output, activation of beta oxidation by muscle, and regulation of the production of the FA-derived bioactive eicosanoids. Thus abnormalities of fat metabolism and the associated pathology might involve dysfunction of CD36-mediated signal transduction in addition to the changes in FA uptake.
Intestinal lipid transport plays a central role in fat homeostasis. Here we review the pathways regulating intestinal absorption and delivery of dietary and biliary lipid substrates, principally ...long-chain fatty acid, cholesterol, and other sterols. We discuss the regulation and functions of CD36 in fatty acid absorption, NPC1L1 in cholesterol absorption, as well as other lipid transporters including FATP4 and SRB1. We discuss the pathways of intestinal sterol efflux via ABCG5/G8 and ABCA1 as well as the role of the small intestine in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. We review the pathways and genetic regulation of chylomicron assembly, the role of dominant restriction points such as microsomal triglyceride transfer protein and apolipoprotein B, and the role of CD36, l-FABP, and other proteins in formation of the prechylomicron complex. We will summarize current concepts of regulated lipoprotein secretion (including HDL and chylomicron pathways) and include lessons learned from families with genetic mutations in dominant pathways (i.e., abetalipoproteinemia, chylomicron retention disease, and familial hypobetalipoproteinemia). Finally, we will provide an integrative view of intestinal lipid homeostasis through recent findings on the role of lipid flux and fatty acid signaling via diverse receptor pathways in regulating absorption and production of satiety factors.
Membrane uptake of long-chain fatty acids (FAs) is the first step in cellular FA utilization and a point of metabolic regulation. CD36 facilitates a major fraction of FA uptake by key tissues. This ...review highlights the contribution of CD36 to pathophysiology in rodents and humans. Novel concepts regarding regulation of CD36-facilitated uptake are discussed (i.e. the role of membrane rafts and caveolae, CD36 recycling between intracellular depots and the membrane, and chemical modifications of the protein that impact its turnover and recruitment). Importantly, CD36 membrane levels and turnover are abnormal in diabetes, resulting in dysfunctional FA utilization. In addition, variants in the CD36 gene were shown recently to influence susceptibility for the metabolic syndrome, which greatly increases the risk of diabetes and heart disease.
Manipulating thermogenesis could increase energy expenditure and improve metabolism. Brown fat is a major site of nonshivering thermogenesis, but other tissues, notably muscle and liver, can ...contribute to cold adaptation. In this issue, Simcox et al. (2017) demonstrate in cold-exposed mice that liver-generated acylcarnitines are required to fuel thermogenesis.
Manipulating thermogenesis could increase energy expenditure and improve metabolism. Brown fat is a major site of nonshivering thermogenesis, but other tissues, notably muscle and liver, can contribute to cold adaptation. In this issue, Simcox et al. demonstrate in cold-exposed mice that liver-generated acylcarnitines are required to fuel thermogenesis.
CD36 is a multifunctional immuno-metabolic receptor with many ligands. One of its physiological functions in the heart is the high-affinity uptake of long-chain fatty acids (FAs) from albumin and ...triglyceride rich lipoproteins. CD36 deletion markedly reduces myocardial FA uptake in rodents and humans. The protein is expressed on endothelial cells and cardiomyocytes and at both sites is likely to contribute to FA uptake by the myocardium. CD36 also transduces intracellular signaling events that influence how the FA is utilized and mediate metabolic effects of FA in the heart. CD36 transduced signaling regulates AMPK activation in a way that adjusts oxidation to FA uptake. It also impacts remodeling of myocardial phospholipids and eicosanoid production, effects exerted via influencing intracellular calcium (iCa2+) and the activation of phospholipases. Under excessive FA supply CD36 contributes to lipid accumulation, inflammation and dysfunction. However, it is also important for myocardial repair after injury via its contribution to immune cell clearance of apoptotic cells. This review describes recent progress regarding the multiple actions of CD36 in the heart and highlights those areas requiring future investigation. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
•Importance of CD36 for cardiac metabolic flexibility•CD36 maintains AMPK quiescent.•Fatty acid uptake signals to upregulate fatty acid oxidation.•Cytosolic calcium and myocardial phospholipid metabolism•CD36 contributes to inflammation and its resolution in the heart.
Lipid uptake and metabolism are central to the function of organs such as heart, skeletal muscle, and adipose tissue. Although most heart energy derives from fatty acids (FAs), excess lipid ...accumulation can cause cardiomyopathy. Similarly, high delivery of cholesterol can initiate coronary artery atherosclerosis. Hearts and arteries-unlike liver and adrenals-have nonfenestrated capillaries and lipid accumulation in both health and disease requires lipid movement from the circulation across the endothelial barrier. This review summarizes recent in vitro and in vivo findings on the importance of endothelial cell receptors and uptake pathways in regulating FAs and cholesterol uptake in normal physiology and cardiovascular disease. We highlight clinical and experimental data on the roles of ECs in lipid supply to tissues, heart, and arterial wall in particular, and how this affects organ metabolism and function. Models of FA uptake into ECs suggest that receptor-mediated uptake predominates at low FA concentrations, such as during fasting, whereas FA uptake during lipolysis of chylomicrons may involve paracellular movement. Similarly, in the setting of an intact arterial endothelial layer, recent and historic data support a role for receptor-mediated processes in the movement of lipoproteins into the subarterial space. We conclude with thoughts on the need to better understand endothelial lipid transfer for fuller comprehension of the pathophysiology of hyperlipidemia, and lipotoxic diseases such as some forms of cardiomyopathy and atherosclerosis.
The precise orosensory inputs engaged for dietary lipids detection in humans are unknown. We evaluated whether a common single nucleotide polymorphism (rs1761667) in the CD36 gene that reduces CD36 ...expression and the addition of orlistat, a lipase inhibitor, to reduce FA release from triacylglycerols (TGs), the main component of dietary fats, would attenuate fat orosensory sensitivity in humans. Twenty-one obese subjects with different rs1761667 genotypes (6 AA, 7 AG, and 8 GG) were studied on two occasions in which oleic acid and triolein orosensory detection thresholds were measured using emulsions prepared with and without orlistat. Subjects homozygous for the G-allele had 8-fold lower oral detection thresholds for oleic acid and triolein than subjects homozygous for the A allele, which associates with lower CD36 expression (P = 0.03). Thresholds for heterozygous subjects were intermediate. The addition of orlistat increased detection thresholds for triolein (log threshold =−0.3 ± 0.2 vs. 0.3 ± 0.1; P < 0.001) but not oleic acid (log threshold =−1.0 ± 0.2 vs. −0.8 ± 0.2; P > 0.2). In conclusion, this is the first experimental evidence for a role of CD36 in fat gustatory perception in humans. The data also support involvement of lingual lipase and are consistent with the concept that FA and not TG is the sensed stimulus.
Long-chain fatty acids (FAs) are components of plasma membranes and an efficient fuel source and also serve as metabolic regulators through FA signaling mediated by membrane FA receptors. Impaired ...tissue FA uptake has been linked to major complications of obesity, including insulin resistance, cardiovascular disease, and type 2 diabetes. Fatty acid interactions with a membrane receptor and the initiation of signaling can modify pathways related to nutrient uptake and processing, cell proliferation or differentiation, and secretion of bioactive factors. Here, we review the major membrane receptors involved in FA uptake and FA signaling. We focus on two types of membrane receptors for long-chain FAs: CD36 and the G protein-coupled FA receptors FFAR1 and FFAR4. We describe key signaling pathways and metabolic outcomes for CD36, FFAR1, and FFAR4 and highlight the parallels that provide insight into FA regulation of cell function.
The prevalence of obesity and type 2 diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates ...glucose uptake in adipose tissue through the GLUT4 (also known as SLC2A4) glucose transporter, and alterations in adipose tissue GLUT4 expression or function regulate systemic insulin sensitivity. Downregulation of human and mouse adipose tissue GLUT4 occurs early in diabetes development. Here we report that adipose tissue GLUT4 regulates the expression of carbohydrate-responsive-element-binding protein (ChREBP; also known as MLXIPL), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose ChREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. We find a new mechanism for glucose regulation of ChREBP: glucose-mediated activation of the canonical ChREBP isoform (ChREBP-α) induces expression of a novel, potent isoform (ChREBP-β) that is transcribed from an alternative promoter. ChREBP-β expression in human adipose tissue predicts insulin sensitivity, indicating that it may be an effective target for treating diabetes.
Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis ...and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.
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