Dynamic role of the transmembrane glycoprotein CD36 (SR-B2) in cellular fatty acid uptake and utilization

The widely expressed transmembrane glycoprotein, cluster of differentiation 36 (CD36), a scavenger receptor class B protein (SR-B2), serves many functions in lipid metabolism and signaling. Here, we review CD36's role in facilitating cellular long-chain fatty acid uptake across the plasma membrane, particularly in heart and skeletal muscles. CD36 acts in concert with other membrane proteins, such as peripheral plasma membrane fatty acid-binding protein, and is an intracellular docking site for cytoplasmic fatty acid-binding protein. The cellular fatty-acid uptake rate is governed primarily by the presence of CD36 at the cell surface, which is regulated by the subcellular vesicular recycling of CD36 from endosomes to the plasma membrane. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly in high-fat diet-induced insulin resistance and diabetic cardiomyopathy. Current research is exploring signaling pathways and vesicular trafficking routes involving CD36 to identify metabolic targets to manipulate the cellular utilization of fatty acids. Because of its rate-controlling function in the use of fatty acids in the heart and muscle, CD36 would be a preferable target to protect myocytes against lipotoxicity. Despite a poor understanding of its mechanism of action, CD36 has emerged as a pivotal membrane protein involved in whole-body lipid homeostasis. The widely expressed transmembrane glycoprotein, cluster of differentiation 36 (CD36), a scavenger receptor class B protein (SR-B2), serves many functions in lipid metabolism and signaling. Here, we review CD36's role in facilitating cellular long-chain fatty acid uptake across the plasma membrane, particularly in heart and skeletal muscles. CD36 acts in concert with other membrane proteins, such as peripheral plasma membrane fatty acid-binding protein, and is an intracellular docking site for cytoplasmic fatty acid-binding protein. The cellular fatty-acid uptake rate is governed primarily by the presence of CD36 at the cell surface, which is regulated by the subcellular vesicular recycling of CD36 from endosomes to the plasma membrane. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly in high-fat diet-induced insulin resistance and diabetic cardiomyopathy. Current research is exploring signaling pathways and vesicular trafficking routes involving CD36 to identify metabolic targets to manipulate the cellular utilization of fatty acids. Because of its rate-controlling function in the use of fatty acids in the heart and muscle, CD36 would be a preferable target to protect myocytes against lipotoxicity. Despite a poor understanding of its mechanism of action, CD36 has emerged as a pivotal membrane protein involved in whole-body lipid homeostasis. Cluster of differentiation 36 (CD36) was first described in 1977 as glycoprotein IV (GP IIIb or GP IV), the fourth major band observed upon SDS-polyacrylamide gel electrophoresis of human platelet membranes (1.Clemetson K.J. Pfueller S.T. Luscher E.F. Jenkins C.S.P. Isolation of the membrane glycoproteins of human platelets by lectin affinity chromatography.Biochim. Biophys. Acta. 1977; 464: 493-508tgCrossref PubMed Scopus (98) Google Scholar). Ten years later, the protein was shown to be identical to the antigen recognized by monoclonal antibody OKM5, a marker for monocytes and macrophages and designated as the leukocyte differentiation antigen CD36 (2.Shaw S. Characterization of human leukocyte differentiation antigens.Immunol. Today. 1987; 8: 1-3Abstract Full Text PDF PubMed Scopus (57) Google Scholar). In that same year, CD36 was reported to be the cellular receptor for thrombospondin (3.Asch A.S. Barnwell J. Silverstein R.L. Nachman R.L. Isolation of the thrombospondin membrane receptor.J. Clin. Invest. 1987; 79: 1054-1061Crossref PubMed Scopus (368) Google Scholar), implicating a role of CD36 in irreversible platelet aggregation, as well as in the adherence of erythrocytes infected with the malaria parasite, Plasmodium falciparum, to the endothelium (4.Ockenhouse C.F. Chulay J.D. Plasmodium falciparum sequestration: OKM5 antigen (CD36) mediates cytoadherence of parasitized erythrocytes to a myelomonocytic cell line.J. Infect. Dis. 1988; 157: 584-588Crossref PubMed Scopus (63) Google Scholar). Subsequently, it was discovered that CD36 is a macrophage receptor for oxidized LDL (oxLDL), thereby establishing its role as a scavenger receptor (5.Endemann G. Stanton L.W. Madden K.S. Bryant C.M. White R.T. Protter A.A. CD36 is a receptor for oxidized low density lipoprotein.J. Biol. Chem. 1993; 268: 11811-11816Abstract Full Text PDF PubMed Google Scholar), and that CD36 acts as facilitator of membrane fatty acid transport (6.Abumrad N.A. El-Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36.J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google Scholar). CD36 is currently known to be a member of a superfamily of scavenger receptor proteins (class B), which also includes scavenger receptor (SR)-B1 and lysosomal integral membrane protein-2 (LIMP-2). These three proteins share their structure, which comprises two transmembrane domains, a relatively large extracellular domain, and both the amino and carboxyl termini located within the cytoplasm (7.Neculai D. Schwake M. Ravichandran M. Zunke F. Collins R.F. Peters J. Neculai M. Plumb J. Loppnau P. Pizarro J.C. et al.Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36.Nature. 2013; 504: 172-176Crossref PubMed Scopus (186) Google Scholar). As a result, CD36 is now officially designated as SR-B2 (8.Prabhudas M. Bowdish D. Drickamer K. Febbraio M. Herz J. Kobzik L. Krieger M. Loike J. Means T.K. Moestrup S.K. et al.Standardizing scavenger receptor nomenclature.J. Immunol. 2014; 192: 1997-2006Crossref PubMed Scopus (144) Google Scholar). Human CD36 has recently been crystallized (9.Hsieh F.L. Turner L. Bolla J.R. Robinson C.V. Lavstsen T. Higgins M.K. The structural basis for CD36 binding by the malaria parasite.Nat. Commun. 2016; 7: 12837Crossref PubMed Scopus (113) Google Scholar). The structure and proposed membrane topology of CD36 are schematically depicted in Fig. 1. CD36 is not expressed ubiquitously, yet is present in a variety of mammalian cell types, including hematopoietic cells (platelets, monocytes, macrophages), endothelial cells, specialized epithelial cells in the breast and eye, enterocytes, and insulin-responsive cells, such as adipocytes, and cardiac and skeletal myocytes. This expression pattern is paralleled by a similar broad number of functions, which are, however, mostly related to the regulation of lipid metabolism and innate immunity. Specifically, CD36 is involved in inflammatory responses and atherothrombotic diseases, intestinal fat absorption, lipid storage in adipose tissue and lipid utilization by cardiac and skeletal muscle, metabolic disorders, such as obesity and diabetes, and Alzheimer's disease [reviewed in (10.Silverstein R.L. Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.Sci. Signal. 2009; 2: re3Crossref PubMed Scopus (714) Google Scholar)]. Interestingly, CD36 is also expressed in human taste bud cells where it functions as a fatty acid sensor acting in oral fat perception and digestive anticipation (11.Laugerette F. Passilly-Degrace P. Patris B. Niot I. Febbraio M. Montmayeur J.P. Besnard P. CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions.J. Clin. Invest. 2005; 115: 3177-3184Crossref PubMed Scopus (502) Google Scholar, 12.Niot I. Besnard P. Appetite control by the tongue-gut axis and evaluation of the role of CD36/SR-B2.Biochimie. 2017; 136: 27-32Crossref PubMed Scopus (11) Google Scholar). In this review, we will summarize our current understanding of the role of CD36 in cellular (long-chain) fatty acid utilization, focusing on the regulation of fatty acid uptake in heart and muscle, the role of CD36 in the pathogenesis of muscular insulin resistance and type 2 diabetes, and the application of CD36 as a target to manipulate cellular fatty acid utilization. From the 1980s onwards, there has been a dispute on the mechanism and regulation of the uptake of (long-chain) fatty acids by parenchymal cells, in particular with respect to the involvement, or not, of membrane-associated proteins in this process (13.Bonen A. Chabowksi A. Luiken J.J.F.P. Glatz J.F.C. Mechanisms and regulation of protein-mediated cellular fatty acid uptake: Molecular, biochemical and physiological evidence.Physiology (Bethesda). 2007; 22: 15-29Crossref PubMed Scopus (196) Google Scholar). While the lipophilic nature of the plasma membrane would allow the rapid passage of fatty acids, from a physiological perspective such free movement of fatty acids in or out of cells without control at the membrane would be undesirable and could seriously hamper coordination of intracellular fatty acid availability with changing metabolic needs (14.Glatz J.F.C. Luiken J.J.F.P. Control of myocardial fatty acid uptake.in: Lopaschuk G.D. Dhalla N.S. Cardiac Energy Metabolism in Health and Disease (Advances in Biochemistry in Health and Disease). Springer Science Inc, New York2014: 49-67Crossref Scopus (5) Google Scholar). In a search for membrane-associated fatty acid transporters, Abumrad and colleagues studied fatty acid uptake into isolated rat adipocytes. Prior incubation of the cells with diisothiocyanodisulfonic acid or with sulfo-N-succinimidyl derivates of long-chain fatty acids (in particular oleate) led to a marked (about 70%) and irreversible inhibition of the rate of fatty acid uptake (15.Harmon C.M. Luce P. Beth A.H. Abumrad N.A. Labeling of adipocyte membranes by sulfo-N-succinimidyl derivatives of long-chain fatty acids: Inhibition of fatty acid transport.J. Membr. Biol. 1991; 121: 261-268Crossref PubMed Scopus (165) Google Scholar, 16.Harmon C.M. Abumrad N.A. Binding of sulfosuccinimidyl fatty acids to adipocyte membrane proteins: Isolation and amino-terminal sequence of an 88-kD protein implicated in transport of long-chain fatty acids.J. Membr. Biol. 1993; 133: 43-49Crossref PubMed Scopus (164) Google Scholar). Both inhibitors reacted covalently with a membrane protein of about 85–88 kDa, suggesting this protein to be involved in membrane permeation of (long-chain) fatty acids. Subsequent cloning of this protein, then referred to as "putative fatty acid translocase" (FAT), revealed it to be the rat homolog of the glycoprotein, CD36 (6.Abumrad N.A. El-Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36.J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google Scholar). The role of FAT/CD36 in facilitating fatty acid uptake by adipocytes was further supported by a superimposed time course of its expression and of oleate uptake rate during adipose differentiation, and by a parallel induction of its expression and oleate transport in preadipocytes following treatment with the glucocorticoid, dexamethasone (6.Abumrad N.A. El-Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36.J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google Scholar). Soon thereafter, a similar role was revealed for CD36 in fatty acid metabolism in cardiac and skeletal muscle (17.Van Nieuwenhoven F.A. Verstijnen C.P. Abumrad N.A. Willemsen P.H. Van Eys G.J. Van der Vusse G.J. Glatz J.F. Putative membrane fatty acid translocase and cytoplasmic fatty acid-binding protein are co-expressed in rat heart and skeletal muscles.Biochem. Biophys. Res. Commun. 1995; 207: 747-752Crossref PubMed Scopus (133) Google Scholar). Several other groups also reported on the identification of peripheral and integral membrane proteins putatively involved in the cellular uptake of fatty acids. These include plasma membrane fatty acid-binding protein (FABPpm; 40–43 kDa), fatty acid transport proteins 1–6 (FATP1–6; 63 kDa), and caveolin-1 (21–24 kDa) [for review see (18.Glatz J.F.C. Luiken J.J.F.P. Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: Implications for metabolic disease.Physiol. Rev. 2010; 90: 367-417Crossref PubMed Scopus (517) Google Scholar, 19.Kazantzis M. Stahl A. Fatty acid transport proteins, implications in physiology and diseases.Biochim. Biophys. Acta. 2012; 1821: 852-857Crossref PubMed Scopus (172) Google Scholar)]. Of these, the FATPs were found to be enzymes, i.e., acyl-CoA synthetases, functioning in cellular fatty acid uptake by converting incoming fatty acids directly into their acyl-CoA ester, resulting in so-called metabolic trapping of fatty acids (19.Kazantzis M. Stahl A. Fatty acid transport proteins, implications in physiology and diseases.Biochim. Biophys. Acta. 2012; 1821: 852-857Crossref PubMed Scopus (172) Google Scholar). However, CD36 appears to be the predominant membrane protein facilitating fatty acid transport, at least in adipocytes, enterocytes, cardiac myocytes, and skeletal myocytes (20.Abumrad N.A. Goldberg I.J. CD36 actions in the heart: lipids, calcium, inflammation, repair and more?.Biochim. Biophys. Acta. 2016; 1861: 1442-1449Crossref PubMed Scopus (67) Google Scholar, 21.Kim T.T. Dyck J.R.B. The role of CD36 in the regulation of myocardial lipid metabolism.Biochim. Biophys. Acta. 2016; 1861: 1450-1460Crossref PubMed Scopus (54) Google Scholar, 22.Glatz J.F.C. Nabben M. Heather L.C. Bonen A. Luiken J.J.F.P. Regulation of the subcellular trafficking of CD36, a major determinant of cardiac fatty acid utilization.Biochim. Biophys. Acta. 2016; 1861: 1461-1471Crossref PubMed Scopus (35) Google Scholar). For instance, in contracting isolated cardiomyocytes, CD36 was found to contribute approximately 70% to the rate of fatty acid uptake (23.Luiken J.J. Willems J. van der Vusse G.J. Glatz J.F. Electrostimulation enhances FAT/CD36-mediated long-chain fatty acid uptake by isolated rat cardiac myocytes.Am. J. Physiol. Endocrinol. Metab. 2001; 281: E704-E712Crossref PubMed Google Scholar). Convincing evidence for a role of CD36 in cellular fatty acid uptake was obtained when studying mice with a targeted deletion of CD36. Compared with wild-type mice, CD36 knockout mice showed reduced fatty acid uptake rates in isolated cardiomyocytes (24.Habets D.D. Coumans W.A. Voshol P.J. den Boer M.A. Febbraio M. Bonen A. Glatz J.F. Luiken J.J. AMPK-mediated increase in myocardial long-chain fatty acid uptake critically depends on sarcolemmal CD36.Biochem. Biophys. Res. Commun. 2007; 355: 204-210Crossref PubMed Scopus (102) Google Scholar), and in vivo in heart (−50% to −80%), skeletal muscle (−40% to −75%), and adipose tissue (−60% to −70%), but not in liver (20.Abumrad N.A. Goldberg I.J. CD36 actions in the heart: lipids, calcium, inflammation, repair and more?.Biochim. Biophys. Acta. 2016; 1861: 1442-1449Crossref PubMed Scopus (67) Google Scholar). Accordingly, in liver, CD36 expression is relatively low (21.Kim T.T. Dyck J.R.B. The role of CD36 in the regulation of myocardial lipid metabolism.Biochim. Biophys. Acta. 2016; 1861: 1450-1460Crossref PubMed Scopus (54) Google Scholar), but can be highly upregulated under hyperlipidemic conditions to contribute to the onset of hepatic steatosis (25.Memon R.A. Fuller J. Moser A.H. Smith P.J. Grunfeld C. Feingold K.R. Regulation of putative fatty acid transporters and acyl-CoA synthetase in liver and adipose tissue in ob/ob mice.Diabetes. 1999; 48: 121-127Crossref PubMed Scopus (81) Google Scholar). For CD36 regulation in liver, the reader is referred to other reviews, e.g., (26.Lee J.H. Zhou J. Xie W. PXR and LXR in hepatic steatosis: a new dog and an old dog with new tricks.Mol. Pharm. 2008; 5: 60-66Crossref PubMed Scopus (52) Google Scholar, 27.He J. Lee J.H. Febbraio M. Xie W. The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease.Exp. Biol. Med. (Maywood). 2011; 236: 1116-1121Crossref PubMed Scopus (88) Google Scholar). These reductions in fatty acid uptake in CD36 knockout mice also contributed to altered rates of fatty acid metabolism, especially with regard to fatty acid oxidation in working hearts and skeletal muscles (22.Glatz J.F.C. Nabben M. Heather L.C. Bonen A. Luiken J.J.F.P. Regulation of the subcellular trafficking of CD36, a major determinant of cardiac fatty acid utilization.Biochim. Biophys. Acta. 2016; 1861: 1461-1471Crossref PubMed Scopus (35) Google Scholar). Similarly, in a group of 47 patients carrying various single nucleotide polymorphisms in the CD36 gene, Tanaka et al. (28.Tanaka T. Nakata T. Oka T. Ogawa T. Okamoto F. Kusaka Y. Sohmiya K. Shimamoto K. Itakura K. Defect in human myocardial long-chain fatty acid uptake is caused by FAT/CD36 mutations.J. Lipid Res. 2001; 42: 751-759Abstract Full Text Full Text PDF PubMed Google Scholar) observed virtually absent fatty acid uptake in vivo in the heart, but no changes in liver. These polymorphisms included insertions of a premature stop codon to result in a truncated protein that is degraded. With respect to nomenclature, it should be mentioned that, for convenience, these proteins commonly are referred to as "fatty acid transporters," despite the remaining uncertainty as to the exact mechanism by which any of these proteins participate in the fatty acid transport process within the plasma membrane. After all, these proteins merely share the feature of facilitating, not necessarily transporting, the transmembrane translocation of (long-chain) fatty acids. Insight into the molecular mechanism by which fatty acids traverse the plasma membrane to enter the soluble cytoplasm has increased markedly in the last decade, especially with respect to the involvement of CD36 [reviewed in (14.Glatz J.F.C. Luiken J.J.F.P. Control of myocardial fatty acid uptake.in: Lopaschuk G.D. Dhalla N.S. Cardiac Energy Metabolism in Health and Disease (Advances in Biochemistry in Health and Disease). Springer Science Inc, New York2014: 49-67Crossref Scopus (5) Google Scholar)]. At the extracellular site, CD36 presumably functions as an acceptor for fatty acids to promote the partitioning of the fatty acids and their delivery to the outer leaflet of the lipid bilayer, most likely in plasma membrane lipid rafts (29.Pohl J. Ring A. Korkmaz U. Ehehalt R. Stremmel W. FAT/CD36-m,ediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts.Mol. Biol. Cell. 2005; 16: 24-31Crossref PubMed Scopus (143) Google Scholar) (adsorption step) (Fig. 1, Fig. 2). Subsequently, the fatty acids make their way from the outer to the inner leaflet of the membrane, a process referred to as "flip-flop" (the polar carboxyl group of the fatty acid moves through the bilayer interior and repositions at the opposite interface) (translocation step). This latter process occurs very fast and would not need assistance from membrane proteins (30.Hamilton J.A. New insights into the roles of proteins and lipids in membrane transport of fatty acids.Prostaglandins Leukot. Essent. Fatty Acids. 2007; 77: 355-361Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). At the inner side of the membrane, the fatty acids move into the aqueous phase to bind to cytoplasmic FABP (FABPc) (desorption step). Desorption from the membrane has been suggested to be the rate-limiting step of overall transmembrane transport (30.Hamilton J.A. New insights into the roles of proteins and lipids in membrane transport of fatty acids.Prostaglandins Leukot. Essent. Fatty Acids. 2007; 77: 355-361Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). At the intracellular side, CD36 may facilitate the transport by providing a docking site for FABPc (31.Spitsberg V.L. Matitashvili E. Gorewit R.C. Association and coexpression of fatty-acid-binding protein and glycoprotein CD36 in the bovine mammary gland.Eur. J. Biochem. 1995; 230: 872-878Crossref PubMed Scopus (148) Google Scholar) or for enzymes that act on fatty acids, such as acyl-CoA synthetase (32.Schneider H. Staudacher S. Poppelreuther M. Stremmel W. Ehehalt R. Füllekrug J. Protein mediated fatty acid uptake: synergy between CD36/FAT-facilitated transport and acyl-CoA synthetase-driven metabolism.Arch. Biochem. Biophys. 2014; 546: 8-18Crossref PubMed Scopus (29) Google Scholar). In line with this, intracellularly, the presence of FABPc is required for proper functioning of CD36, as it was reported that transfection of CD36 in a rat heart muscle cell line (H9c2) devoid of FABPc did not result in increased rates of fatty acid uptake (33.Van Nieuwenhoven F.A. Luiken J.J.F.P. De Jong Y.F. Grimaldi P.A. Van der Vusse G.J. Glatz J.F.C. Stable transfection of fatty acid translocase (CD36) in a rat heart muscle cell line (H9c2).J. Lipid Res. 1998; 39: 2039-2047Abstract Full Text Full Text PDF PubMed Google Scholar). Taken together, CD36 is viewed to function in sequestering fatty acids in the membrane, and helping to organize them within specific membrane domains (presumably lipid rafts) in order to make the fatty acids readily available for subsequent aqueous transport and/or enzymic conversion (Fig. 2). Interestingly, there is evidence to suggest that at the extracellular side, CD36 displays protein-protein interaction with FABPpm (34.Chabowski A. Górski J. Luiken J.J.F.P. Glatz J.F.C. Bonen A. Evidence for a concerted action of FAT/CD36 and FABPpm to increase fatty acid transport across the plasma membrane.Prostaglandins Leukot. Essent. Fatty Acids. 2007; 77: 345-353Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar), possibly indicating that clusters of membrane proteins function in facilitating and modulating cellular fatty acid uptake. A concerted action among these various proteins may allow a fine-tuning of fatty acid transport so as to have this substrate readily available for efficient intracellular utilization (18.Glatz J.F.C. Luiken J.J.F.P. Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: Implications for metabolic disease.Physiol. Rev. 2010; 90: 367-417Crossref PubMed Scopus (517) Google Scholar). Recent crystallization studies have shed more light on the mechanism of fatty acid transport by CD36. First, LIMP-2 was crystallized, and based on the close similarity with CD36, it was deduced that CD36 possesses a cavity running through the entire length of the protein through which the fatty acids can be transferred to the lipid bilayer (7.Neculai D. Schwake M. Ravichandran M. Zunke F. Collins R.F. Peters J. Neculai M. Plumb J. Loppnau P. Pizarro J.C. et al.Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36.Nature. 2013; 504: 172-176Crossref PubMed Scopus (186) Google Scholar). This would then provide the molecular basis for the adsorption step. Further support for such a cavity comes from crystallization of CD36 when bound to fatty acids (Fig. 1B) (9.Hsieh F.L. Turner L. Bolla J.R. Robinson C.V. Lavstsen T. Higgins M.K. The structural basis for CD36 binding by the malaria parasite.Nat. Commun. 2016; 7: 12837Crossref PubMed Scopus (113) Google Scholar). The cavity was shown to contain up to two fatty acids at a time, thereby indicating that CD36 truly acts as a fatty acid transporter whereby fatty acids pass through the CD6 ectodomain to be exposed to the plasma membrane surface (Fig. 1B). These crystallization studies add powerful support to the fatty acid transport function of CD36. Whether CD36 would preferentially bind specific (long-chain) fatty acid types has remained elusive. This is due, at least in part, to the complexity of appropriate experimental approaches, which would need to consider, among others, differences among fatty acid types in aqueous solubility and differences in interaction with soluble proteins (such as albumin) and with biological membranes. Of note, there is circumstantial evidence that the cellular uptake of fatty acid species from marine oils, in particular EPA (20:5 n-3) and DHA (22:6 n-3), is also facilitated by CD36 (35.Franekova V. Angin Y. Hoebers N.T. Coumans W.A. Simons P.J. Glatz J.F. Luiken J.J. Larsen T.S. Marine omega-3 fatty acids prevent myocardial insulin resistance and metabolic remodeling as induced experimentally by high insulin exposure.Am. J. Physiol. Cell Physiol. 2015; 308: C297-C307Crossref PubMed Scopus (17) Google Scholar, 36.Glatz J.F. Luiken J.J. Fatty acids in cell signaling: historical perspective and future outlook.Prostaglandins Leukot. Essent. Fatty Acids. 2015; 92: 57-62Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), suggesting that the beneficial health effects of n-3 long-chain polyunsaturated fatty acids are dependent on the sarcolemmal presence and proper functioning of CD36. The observation that CD36 is not only present on the cell membrane but also in intracellular compartments, notably endosomes, has triggered a series of studies, which revealed that CD36 is not merely a facilitator of transmembrane fatty acid transport, but in fact serves a pivotal role as regulator of the rate of cellular fatty acid uptake. Thus, it was disclosed that regulation of fatty acid transport occurs by the reversible translocation of CD36 from endosomes to the plasma membrane to increase fatty acid uptake. For instance, in both cardiac and skeletal muscle, the portion of CD36 that is stored in endosomes is estimated to be approximately 50% (37.Bonen A. Luiken J.J.F.P. Arumugam Y. Glatz J.F.C. Tandon N.N. Acute regulation of fatty acid uptake involves the cellular redistribution of fatty acid translocase.J. Biol. Chem. 2000; 275: 14501-14508Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, 38.Luiken J.J.F.P. Koonen D.P. Willems J. Zorzano A. Becker C. Fisher Y. Tandon N.N. van der Vusse G.J. Bonen A. Glatz J.F.C. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36.Diabetes. 2002; 51: 3113-3119Crossref PubMed Scopus (212) Google Scholar). Either an increase in muscle contraction or the presence of insulin each stimulate, within a few minutes, the translocation of CD36 from the endosomal compartment to the sarcolemma upon which the fatty acid uptake rate increases up to 2-fold (37.Bonen A. Luiken J.J.F.P. Arumugam Y. Glatz J.F.C. Tandon N.N. Acute regulation of fatty acid uptake involves the cellular redistribution of fatty acid translocase.J. Biol. Chem. 2000; 275: 14501-14508Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, 38.Luiken J.J.F.P. Koonen D.P. Willems J. Zorzano A. Becker C. Fisher Y. Tandon N.N. van der Vusse G.J. Bonen A. Glatz J.F.C. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36.Diabetes. 2002; 51: 3113-3119Crossref PubMed Scopus (212) Google Scholar, 39.Luiken J.J.F.P. Coort S.L.M. Willems J. Coumans W.A. Bonen A. van der Vusse G.J. Glatz J.F.C. Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling.Diabetes. 2003; 52: 1627-1634Crossref PubMed Scopus (229) Google Scholar). The process of contraction-induced CD36 translocation is mediated by AMP-activated kinase (39.Luiken J.J.F.P. Coort S.L.M. Willems J. Coumans W.A. Bonen A. van der Vusse G.J. Glatz J.F.C. Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling.Diabetes. 2003; 52: 1627-1634Crossref PubMed Scopus (229) Google Scholar). Insulin-induced translocation is mediated by phosphoinositide-3-kinase (38.Luiken J.J.F.P. Koonen D.P. Willems J. Zorzano A. Becker C. Fisher Y. Tandon N.N. van der Vusse G.J. Bonen A. Glatz J.F.C. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36.Diabetes. 2002; 51: 3113-3119Crossref PubMed Scopus (212) Google Scholar). Insulin and contraction signaling operate independently to induce CD36 translocation, but converge at the level of the Rab GTPase-activating protein, AS160, via an inactivating phosphorylation. This leads to disinhibition of Rab 8a, which is then allowed to use the accelerated GDP/GTP cycling for the benefit of CD36 translocation (40.Samovski D. Su X. Xu Y. Abumrad N.A. Stahl P.D. Insulin and AMPK regulate FA translocase/CD36 plasma membrane recruitment in cardiomyocytes via Rab GAP AS160 and Rab8a Rab GTPase.J. Lipid Res. 2012; 53: 709-717Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Remarkably, this mechanism of regulation of cellular fatty acid uptake by recycling of CD36 is very similar to the well-known regulation of cellular glucose uptake, which, in cardiac and skeletal muscle, involves the translocation of glucose transporter-4 (GLUT4) from an intracellular storage depot to the sarcolemma (41.Klip A. Sun Y. Chiu T.T. Foley K.P. Signal transduction meets vesicle traffic: the software and hardware of GLUT4 translocation.Am. J. Physiol. Cell Physiol. 2014; 306: C879-C886Crossref PubMed Scopus (128) Google Scholar). Upon increased muscle contraction or insulin stimulation, both CD36 and GLUT4 are recruited to the sarcolemma within the same time frame resulting in increased uptake rates for both fatty acids and glucose (18.Gla