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CD36: Implications in Cardiovascular Disease


CD36 is a broadly expressed membrane glycoprotein that acts as a facilitator of fatty acid uptake, a signaling molecule, and a receptor for a wide range of ligands, including apoptotic cells, modified forms of low density lipoprotein, thrombospondins, fibrillar beta-amyloid, components of gram positive bacterial walls and malaria infected erythrocytes. CD36 expression on macrophages, dendritic and endothelial cells, and in tissues including muscle, heart, and fat, suggest diverse roles, and indeed, this is truly a multifunctional receptor involved in both homeostatic and pathologic conditions. Despite an impressive increase in our knowledge of CD36 functions, in depth understanding of the mechanistic aspects of this protein remains elusive. This review focuses on CD36 in cardiovascular disease—what we know, and what we have yet to learn.


In the last 30 years, study of CD36 has led to a deep appreciation of its multi-functionality. First described on platelets and named glycoprotein IV (GPIV) (Tandon, Lipsky, Burgess & Jamieson, 1989), it was subsequently discovered as a macrophage receptor for oxidized LDL (CD36) (Endemann, Stanton, Madden, Bryant, White, & Protter, 1993) and as an adipocyte fatty acid transporter (FAT) (Abumrad, el-Maghrabi, Amri, Lopez, & Grimaldi, 1993). We now know that the broad expression pattern of CD36 is mirrored by its equally broad list of functions. In the last 5 years, CD36 has figured prominently in the fields of cardiovascular function and disease (Ma, et al. 2004, Kuang, Febbraio, Wagg, Lopaschuk, & Dyck, 2004), parasitology (Franke-Fayard, et al., 2005), cancer biology (Huang, et al., 2004), Alzheimer's disease (Moore, et al., 2004), stroke (Cho, et al., 2005) angiogenesis (Simantov, Febbraio, & Silverstein, 2005), diabetes (Corpeleijn, et al., 2006, Lepretre, et al., 2004), platelet biology (Englyst, Taube, Aitman, Baglin, & Byrne, (2003), muscle function and metabolism (Koonen, Glatz, Bonen and Luiken, 2005), and even food choice (Laugerette, et al., 2005). The creation of the CD36 knock out (KO) mouse and subsequent crossing to other murine mutants has enabled many of these studies (Febbraio, et al., 1999). Apart from a recent publication (Moore, et al., 2005) suggesting that CD36 expression is beneficial in the pathogenesis of atherosclerosis (which we will address specifically), the consensus of the literature is that macrophage CD36 plays a major role in the uptake of pro-atherogenic lipoproteins, and in the absence of up-regulation of efflux mechanisms, this results in foam cell formation, the initiating lesion in atherosclerosis. This review will focus on CD36 as it relates to the cardiovascular system, and thus is not meant to be exhaustive and will omit ligands and functions that may not be pertinent to this focus. It will also look to what is yet to be learned about CD36 as it relates to cardiovascular function and disease.

CD36 Structure and Expression

The scope of functions attributed to CD36 is remarkable in the context of its structure. CD36 is an 88 Kd ditopic heavily N-linked glycosylated membrane protein (Gruarin, Thorne, Dorahy, Burns, Sitia, and Alessio, 2000). The human CD36 gene is currently reported to extend about 28 kb on chromosome 7q (XenneX, Inc., GeneCards, Fernandez-Ruiz, Armesilla, Sanchez-Madrid, & Vega, 1993, Wyler, Daviet, Bortkiewicz, Bordet, & McGregor, 1993) and encodes a predicted protein of 471 amino acids with a predicted molecular weight of 52,922 Da (XenneX, Inc., GeneCards). Other putative promoter and exons have been identified, thus the gene size may change. Human CD36 has a large extracellular domain characterized by 10 N-linked glycosylation sites, and as a result the actual molecular weight varies from ∼80−90 kDa (Oquendo, Hundt, Lawler, & Seed, 1989). Variant transcripts have been identified, as have a multitude of (predominantly) non-coding single nucleotide polymorphisms (NCBI single nucleotide polymorphism (SNP) database, Wyler, Daviet, Bortkiewicz, Bordet, & McGregor, 1993, Taylor, Tang, Sobieski, & Lipsky, 1993, Gelhaus, Scheding, Browne, Burchard, & Horstmann, 2001). Mutations which result in absence of CD36 expression in platelets (Type I CD36 deficiency) or in all cells (Type II CD36 deficiency) have been characterized, and are found in Asian and African populations predominantly (Yamamoto, Akamatsu, Sakuraba, Yamazaki, & Tanoue, 1994, Lee, et al., 1999). There is some suggestion of selective pressure from the malaria parasite, Plasmodium falciparum for these mutations, but whether absence of CD36 is protective against the lethality of the parasite remains controversial (Aitman, et al., 2000, Serghides, Smith, Patel, & Kain, 2003). Extracellular CD36 is characterized by a hydrophobic domain that may extend into the plasma membrane. Binding sites for fatty acids (Baillie, Coburn, & Abumrad, 1996), thrombospondin-1 (Pearce, Wu, & Silverstein, 1995), modified low density lipoprotein (LDL) (Pearce, Roy, Nicholson, Hajjar, Febbraio, & Silverstein, 1998) and the growth hormone releasing peptide, (GHRP) hexarelin (Demers, et al., 2004) have been mapped. An immuno dominant domain (amino acids 155−183, Daviet, Buckland, Puente Navazo, M.D. & McGregor, 1995) has also been implicated in binding apoptotic cells (Navazo, Daviet, Savill, Ren, Leung, & McGregor, 1996) and modified LDL (Puente Navazo, Daviet, Ninio, & McGregor, 1996), but because antibody binding to this domain disrupts all CD36 functions, it may relate more to conformational change of the receptor than actual binding site for these ligands. An interesting property of CD36 is the ectophosphorylation of threonine 92 which has been shown to impact binding of certain ligands (Asch, et al., 1993, Hatmi, Gavaret, Elalamy, Vargaftig, & Jacquemin, 1996, Ho, et al., 2005). The intracellular domains of CD36 are located on very short cytoplasmic tails: the N-terminal tail is probably the result of an uncleaved signal peptide. Both tails are characterized by a pair of cysteine residues that are palmitoylated (Jochen, & Hays, 1993, Tao, Wagner, & Lublin, 1996) and these are important in positioning CD36 in caveolae and lipid rafts. Both the N-terminal and the C-terminal cytoplasmic domains have been shown to be important for efficient plasma membrane CD36 expression (Gruarin, Thorne, Dorahy, Burns, Sitia, & Alessio,. 2000, Eyre, Cleland, Tandon, & Mayrhofer, 2006). In some cell types, expression of caveolin-1 has been shown to be necessary for plasma membrane targeting of CD36, and disruption of caveolae may effect some CD36 dependent functions (Ring, Le Lay, Pohl, Verkade, & Stremmel 2006, Vistisen, Roepstorff, Roepstorff, Bonen, van Deurs, & Kiens, 2004, Frank, Lee, Park, Tandon, Scherer, & Lisanti,. 2004, Pohl, Ring, Korkmaz, Ehehalt, & Stremmel, 2005, Kincer, et al., 2002, Dorahy, Lincz, Meldrum, & Burns, 1996). The partitioning of CD36 to specific plasma membrane domains may facilitate interaction with signaling partners that are essential to CD36 dependent responses. What is notably absent from CD36 structure are clear cut domains that are associated with kinases, adaptor proteins, or motifs that may specify interaction with other proteins.

CD36 is expressed on an extensive range of cells and tissues, including microvascular endothelial cells (Swerlick, Lee, Wick, & Lawley, 1992), monocytes and macrophages (Endemann, Stanton, Madden, Bryant, White, and Protter, 1993, Huh, Pearce, Yesner, Schindler, & Silverstein, 1996), dendritic cells (Rouabhia, Jobin, Doucet, Jr., Bergeron, & Auger, 1994, Albert, et al., 1998), adipocytes (Abumrad, el-Maghrabi, Amri, Lopez, & Grimaldi, 1993), keratinocytes (Allen, Barker, & MacDonald, 1991), cardiac and skeletal muscle (Van Nieuwenhoven, et al., 1995), retinal pigment epithelium (Ryeom, Sparrow, & Silverstein, 1996), microglia (Husemann, Loike, Anankov, Febbraio, & Silverstein, 2002), reticulocytes (Sugihara, Sugihara, Mohandas, & Hebbel, 1992), breast, (Clezardin, Frappart, Clerget, Pechoux, & Delmas, 1993), gut (Chen, Yang, Braunstein, Georgeson, & Harmon, 2001), and renal epithelium (Susztak, Ciccone, McCue, Sharma, & Bottinger, 2005), and platelets (Bolin, Medina, & Cheney 1981). More recently, expression has been reported on hepatocytes under certain circumstances (Vosper, et al., 2001, Yu, et al., 2001, Zhou, et al., 2006) and smooth muscle cells (Lim, et al., 2006, de Oliveira Silva, Delbosc, Arais, Monnier, Cristol, & Pares-Herbute, 2006, Kwok, Juan, and Ho, 2006). CD36 plays a role in uptake of apoptotic cells (Savill, Hogg, Ren, and Haslett, 1992), shed photoreceptor outer segments (Ryeom, Sparrow, & Silverstein, 1996), and modified lipoproteins (Endemann, Stanton, Madden, Bryant, White, & Protter, 1993, Podrez, et al.,2000), and in recognition of ligands that trigger an innate immune response, including components of gram positive bacteria cell walls (Hoebe, et al., 2005, Stuart, et al., 2005) (as a co-receptor with Toll Like Receptor (TLR) 2), fibrillar amyloid β (Bamberger, Harris, McDonald, Husemann, & Landreth, 2003, El Khoury, et al., 2003), which is a constituent of Alzheimer plaque, and resembles fibrillar amyloid protein (Medeiros, et al., 2004), that may occur in atherosclerotic plaque. In addition to facilitating fatty acid transport into adipocytes and cardiac and skeletal muscle (and perhaps other cells), CD36 was recently shown to be a sensor for fatty acids in taste buds, eliciting a secretory response in the gut (Laugerette, et al., 2005). CD36 interacts with ligands which contain a thrombospondin 1 (TSP-1) type 1 repeat element (TSR) to inhibit a pro-angiogenic signal, resulting in endothelial cell apoptosis (Dawson, Pearce, Zhong, Silverstein, Frazier, & Bouck, 1997, Dawson, et al., 1999, Jimenez, Volpert, Crawford, Febbraio, Silverstein, & Bouck, 2000, Miao, Seng, Duquette, Lawler, Laus, & Lawler, 2001, Simantov, Febbraio & Silverstein, 2005).

CD36 is presumed to be an endocytic receptor for most ligands with the exception of long chain fatty acids, where it may facilitate their transfer across the lipid membrane, but this remains a poorly defined process. It is possible that CD36 directly interacts with fatty acids (a binding site has been broadly mapped) and/or this is coupled with cytoplasmic fatty acid binding proteins for efficient translocation (Glatz, Bonen, & Luiken, 2002, Spitsberg, Matitashvili, & Gorewit, 1995), or that CD36 is a member of a specific plasma membrane domain that has increased permeability to fatty acids, and CD36 may “corral” fatty acids to this domain for efficient translocation (this could also be coupled to cytoplasmic fatty acid binding proteins). It is also possible that CD36 oligomerizes to form a pore. Whatever the mechanism, absence of CD36 affects fatty acid uptake by various tissues, including adipocytes and muscle, and this leads to measurable phenotype (Febbraio, et al., 1999). CD36 KO mice have a fasting hypoglycemia and different energy substrate use in heart (Kuang, Febbraio, Wagg, Lopaschuk, & Dyck, 2004). Uptake of fatty acid analogs was specifically reduced in muscle and adipocytes of mice, and has been shown to be reduced in heart of CD36-deficient humans (Coburn, Knapp, Febbraio, Beets, Silverstein, & Abumrad, 2000, Watanabe, et al., 1998, Hwang, et al., 1998, Tanaka, et al. 2001).

CD36 Ligands and Functions

CD36 was originally identified as a receptor for TSP-1, a large trimeric multi-domain extracellular matrix protein that has a diverse range of functions, some of which are CD36 dependent (Kieffer, Nurden, Hasitz, Titeux, & Breton-Gorius, 1988, Adams & Lawler, 2004). One function of this receptor-ligand pair with relevance to cardiovascular biology and pathology is inhibition of angiogenesis (Dawson, Pearce, Zhong, Silverstein, Frazier, & Bouck, 1997). Angiogenesis is the body's response to ischemia and vascular injury, and work has demonstrated that oxidatively modified LDL (oxLDL) which may be found in hyperlipidemic states, including atherosclerosis, diabetes and the metabolic syndrome, can inhibit endothelial cell proliferation and angiogenesis (Chen, et al., 1997, Imanishi, Hano, Matsuo, & Nishio, 2003, Mwaikambo, Sennlaub, Ong, Chemtob, & Hardy, 2006). Hyperlipidemia has also been shown to delay arteriogenesis in hypercholesterolemic mice (Henry, 1993, Tirziu, et al., 2005, van Weel, et al., 2006). Interestingly, oxLDL up regulates CD36 expression via peroxisome proliferator activated receptor (PPAR) γ, and this may contribute to inhibition of angiogenesis by initiating a feed forward loop of CD36 expression that amplifies the anti-angiogenic affect observed in these states (Tontonoz, Nagy, Alvarez, Thomazy, & Evans, 1998). Thus, in a hyperlipidemic setting, expression of CD36 may play a role in ischemia, and may contribute to ischemia in the aftermath of myocardial infarction and stroke. Inhibition of angiogenesis by exploiting this pathway has led to the development of TSP-1 peptides and mimetics that are currently in clinical trials for application in cancer and diabetic retinopathy (Dawson, et al., 1999, Rusk, et al., 2006, Gietema, et al., 2006). The idea of up regulation of CD36 to inhibit angiogenesis by TSP-1 has been explored to increase the efficacy of the anti-angiogenic effect in a tumor model (Huang, et al., 2004). CD36-TSP-1 interaction is also important in maintenance of an anti-inflammatory milieu in the uptake of apoptotic cells as a homeostatic process, and during wound resolution (see later).

CD36 is classified as a class B scavenger receptor (Platt, & Gordon, 1998, Krieger, 1997), and is part of a gene family that includes lysosomal integral membrane protein II (LIMP-II), which plays a role in nerve myelinization (Gamp, et al., 2003), CD36 and LIMP-II analogous-I protein (CLA-1) (known as scavenger receptor BI (SR-BI) in mice), which mediates the selective uptake of cholesterol esters from high density lipoprotein (HDL) (Acton, Rigotti, Landschulz, Xu, Hobbs, & Krieger, 1996), and Croquemorte, a drosophila protein, that phagocytoses apoptotic cells and senescent erythrocytes (Franc, Dimarcq, Lagueux, Hoffmann, & Ezekowitz, 1996, Franc, Heitzler, Ezekowitz, & White, 1999). Scavenger receptors are found in both primitive and immunologically advanced organisms and their continued evolutionary conservation suggest their important role at the forefront of the initial organism response to pathogens and in normal homeostasis (Krieger, 1997, Gordon, 2002). For example, BLAST analysis reveals CD36 homologues in fly, worm and sponge, and based on the functions of these relatives, we can speculate that uptake of apoptotic cells is the most ancient function of CD36. CD36 recognizes and binds apparent pattern motifs which are often non-protein repetitive molecules, such as found on the outer membranes or walls of bacteria. Hoebe, et al. (2005) characterized a recessive mutation in N-ethyl-N-nitrosurea (enu) mutated mice which did not respond to some TLR 2/6 ligands, and showed it to be within the CD36 gene, resulting in absent expression (oblivious mice). Interestingly, they found that CD36 was a necessary co-receptor for TLR 2 ligands containing diacylglycerides but not triacylglycerides. Recently, there has been some controversy about the exact nature of the ligand on gram positive bacteria. Hoebe et al. reported it to be lipoteichoic acid, but one group argues that the actual ligand is a lipoprotein that co-isolates with lipoteichoic acid, and that when bacteria are mutated such that the lipoprotein cannot be biosynthesized, the resulting lipoteichoic acid has only 1/100 of the activating properties as lipoprotein (Hashimoto, et al., 2006). Whether lipoprotein or lipoteichoic acid, macrophages from CD36 KO mice were less efficient at phagocytosis of gram positive Staphylococcus aureus, less able to clear infection, and more susceptible to abscess and death (Stuart, et al., 2005).

Scavenger receptors also recognize modified lipoproteins, which may arise as byproducts during an inflammatory response or by other mechanisms. In terms of modified LDL, the exact nature of the CD36 ligand has been recently defined as a truncated phosphatidylcholine species, with a specific sn-2 esterified γ-hydroxy (or oxo) – α,β-unsaturated carbonyl containing fatty acid (Podrez, et al., 2002a, Podrez, et al., 2002b). These modifications can occur as a result of the action of reactive oxygen or nitrogen species. CD36 has also been reported to bind HDL and very low density lipoprotein (VLDL), but the nature of the ligand on these lipoproteins has not been characterized (Calvo, Gomez-Coronado, Suarez, Lasuncion, & Vega, 1998). Binding and uptake of modified LDL may have arisen as a homeostatic response of macrophages, and would have protected the organism from pathology associated with these aberrant lipoproteins. In our Western civilization, this function apparently is inadequate to keep pace with the heavy lipid load from our diet and thus atherosclerosis results.

In addition to protection against pathogens and clearance of aberrant lipoproteins, scavenger receptors also protect the host against inflammation in the setting of the normal turnover of cells by apoptosis and during wound resolution. Apoptotic cell membranes lose asymmetry, such that the outer membrane becomes enriched in anionic phosphatidylserine (Pittoni, & Valesini, 2002). Indeed, previous work identified phosphatidylserine species as the ligand for CD36, but those earlier studies were done without attention paid to the potential for oxidative changes (Fadok, Bratton, Frasch, Warner, & Henson, 1998, Ryeom, Silverstein, Scotto, & Sparrow, 1996). Greenberg, et al. (2006) demonstrated that the same oxidative changes that occur in phosphatidylcholine species of lipoproteins, which generate specific structures that are recognized by CD36, can analogously occur in phosphatidylserine species of apoptotic cells. These are specifically recognized by CD36, and not competed by non-oxidized phosphatidylserine. Similarly, but unrelated to vascular biology, the docosahexanenoic acid of 2-lyso-phosphatidylcholine, which is enriched in rod outer segments in the retina, are photo oxidized to generate analogous sn-2 esterified γ-hydroxy (or oxo) – α,β-unsaturated carbonyl containing fatty acids, and this creates a recognition signal for CD36 expressed on retinal pigment epithelium for phagocytosis (Sun, et al., 2006). These studies established that the truncated fatty acid needs to be in the context of a phospholipid in order to be recognized and signal phagocytosis. Understanding the structural properties of ligands for CD36 represents one of the major advances in CD36 biology over the last 5 years, and will be essential to assessing the physiologic role of CD36, as well as provide insight into design of therapeutics.

CD36 also interacts with advanced glycation end products (AGE) (Ohgami, et al., 2001), which are generated in diabetes and chronic inflammatory settings such as atherosclerosis (Forbes, Soldatos, & Thomas, 2005, Brownlee, 2005, Basta, Schmidt, & De Caterina, 2004). Advanced glycation end products are protein adducts which are thought to accumulate, and thus may form a repetitive motif recognized by CD36 and other scavenger receptors.

Another ligand for CD36 is the GHRP, hexarelin, and a derivative with no growth hormone releasing properties, EP 80317 (Bodart, et al., 2002). Previous work had shown that hexarelin pretreatment of growth hormone deficient rats protected against cardiac damage in ischemia/reperfusion models. Because this affect could be separated from growth hormone effects, it was hypothesized that it was due to a cardiac specific receptor. Using a photoactivatable derivative of hexarelin to cross-link it to the putative receptor in heart, CD36 was identified (Demers, et al., 2004). Cross-linking experiments using hearts from CD36 KO mice showed no binding partner. In an isolated perfused heart system, hexarelin induced a dose dependent vasoconstriction that again was not observed in hearts from CD36 KO mice and spontaneous hypertensive rats (SHR), which have also been shown to lack CD36 (Bodart, et al., 2002). Detailed mapping by enzymatic and chemical degradation showed that the binding site for hexarelin overlapped with the oxLDL site and the apparent point of contact was methionine 169 (Demers, et al., 2004). This observation led to the hypothesis that hexarelin or EP 80317 could interfere with oxLDL binding and perhaps have a protective effect in atherosclerosis (see later).

Modulation of the binding of platelets to collagen and thrombospondin-1, and the binding of Plasmodium falciparum infected erythrocytes to microvascular endothelium has been shown to be regulated by phosphorylation/dephosphorylation of the ectodomain of CD36, specifically, threonine 92 (Asch, et al. 1993, Ho, et al., 2005). Asch et al. found that resting platelets constitutively express phosphorylated CD36, and have greater affinity for collagen compared to TSP-1. Initial low affinity interaction between CD36 and TSP-1 results in platelet degranulation and the release of phosphatases that can dephosphorylate CD36, resulting in higher affinity binding of TSP-1. Similarly, Ho et al. showed that microvascular endothelial CD36 is constitutively expressed in the phosphorylated form. Interaction with falciparum infected erythrocytes resulted in src family kinase activation, and subsequent activation of an endothelial cell surface phosphatase which led to higher affinity for infected erythrocytes under flow conditions. This novel mechanism of modulation of ligand binding has important implications in vascular biology, including thrombosis mediated by platelet aggregation and angiogenesis, but has largely been unexplored.

CD36 Signaling

Despite its short cytoplasmic domains, it has become apparent that CD36 is a signaling molecule. As mentioned above, interaction of CD36 with TSP-1 has potent anti-angiogenic effect. Structure-function analyses have mapped the domain on TSP-1 responsible for this effect to the type I repeat (Iruela-Arispe, Lombardo, Krutzsch, Lawler, & Roberts, 1999) and other proteins such as TSP-2, which contain this domain, are also anti-angiogenic in a CD36 dependent manner (Simantov, Febbraio, & Silverstein, 2005). On CD36, the TSP-interacting domain has been mapped to the CLESH-1 domain (CD36, LIMPII, emp, SR-BI homology) which is also present in other proteins (Crombie, & Silverstein, 1998). Work from our lab in collaboration with Noel Bouck demonstrated that in endothelial cells, when CD36 binds to TSP-1 there is association with and phosphorylation of the src kinase fyn, and this leads to downstream phosphorylation of caspases and the mitogen activated protein (MAP) kinase p38, and ultimately cellular apoptosis which prevents angiogenesis (Figure 1a) (Jimenez, Volpert, Crawford, Febbraio, Silverstein, & Bouck, 2000). Primo et al., (2005) using site directed mutagenesis to create C-terminal tail mutants of CD36 expressed in human umbilical vein endothelial cells by a retroviral vector, showed that specific amino acids, cysteine 464, arginine 467 and lysine 469, were essential to the TSP-1 inhibitory activity. They further showed that CD36-TSP-1 interaction led to down regulation of vascular endothelial growth factor (VEGF) receptor 2 and the p38 mediated phosphorylation induced by VEGF-A165, and this was dependent upon cysteine 464.

Figure 1Figure 1Figure 1
Binding of ligands to CD36 leads to cell specific activation of signaling pathways and responses. (A) Binding of TSR containing ligands of CD36, such as thrombospondin-1, leads to a specific signaling cascade involving the src kinase fyn, caspases and ...

Apoptotic cell phagocytosis can be functionally separated from signaling events that are anti-inflammatory, and there appear to be multiple redundant pathways (Lucas, et al. 2006). One pathway, however, involves CD36-TSP-1 interaction, and reminiscent of what occurs in endothelial cells, this interaction can interrupt another signal—in this case a lipopolysaccharide (LPS) induced pro-inflammatory cascade (Voll, Herrmann, Roth, Stach, Kalden, & Girkontaite, 1997). The details of these events are yet to be elucidated, but the result is secretion of IL-10, an anti-inflammatory cytokine, and inhibition of secretion of the pro-inflammatory cytokines TNF-α, IL-12 and IL-1β.

In contrast, binding of β-amyloid by microglia expressing CD36 (in conjunction with α6β1 integrin and CD47) leads to assembly of a signaling complex which includes F-actin, fyn, lyn, pax, pyk2 and cas (Figure 1b) (Moore, et al., 2002). This leads to the downstream phosphorylation of p44/42 MAP kinases, and subsequent expression of TNF-α, MCP-1, MIP-1, MIP-2, IL-1β and reactive oxygen species (ROS). The vav guanine nucleotide exchange factor has recently been shown to link this signaling complex to the respiratory burst and phagocytosis in both monocytes and microglia (Figure 1b) (Wilkinson, Koenigsknecht-Talboo, Grommes, Lee, & Landreth, 2006). Similarly, fibrillar amyloid found in atheroma also elicits a CD36-dependent signaling cascade involving lyn and p44/42 MAP kinases, and ultimately CD36-dependent secretion of ROS and TNF-α (Stewart, et al., 2005). Recently, the association between CD36 and lyn has been shown to be lipid-mediated (Thorne, et al, 2006).

In macrophages/dendritic cells, CD36 has been found to be essential to some TLR2/6 responses evoked by extracts of gram positive bacteria (as mentioned above, the exact ligand is currently quite controversial). This leads to the classic TLR signaling cascade resulting in NFκB activation and secretion of TNF-α, IL-6 and IL-12. Triantafilou et al. (2006) showed that heterodimers of TLR2/6 exist preformed in the plasma membrane prior to ligand engagement, but that in contrast, association with CD36 is ligand dependent. The newly formed receptor complex is then recruited to lipid rafts where activation/signaling occurs. Using CD36 mutants, Stuart, et al. (2005) went on to show that phagocytosis of gram positive bacteria was mediated by specific amino acids (tyrosine 463 and cysteine 464) in the C-terminal cytoplasmic tail of CD36, which apparently are necessary for TLR2/6 signaling. In contrast, for binding and capture of oxLDL, the terminal 6 amino acids (467−472) have been implicated (Malaud, Hourton, Giroux, Ninio, Buckland, & McGregor, 2002). The C-terminal cytoplasmic domain has also been implicated in fatty acid uptake (Eyre, Cleland, Tandon, & Mayrhofer, 2006).

We recently demonstrated that macrophage CD36 is necessary for activation of lyn kinase, MEKK2 and ultimately jnk (specifically jnk2 in mice) and this results in phagocytosis of pro-atherogenic LDL (Figure 1c) (Rahaman, Lennon, Febbraio, Podrez, Hazen, & Silverstein, 2006). This pathway is essential for foam cell formation, which is the cellular component of fatty streaks, the initial gross lesion in the pathogenesis of atherosclerosis. Indeed, pharmacological inhibition of jnk or macrophage specific deletion of jnk reduced atherosclerosis in murine models, and atherosclerosis is also reduced in lyn KO mice. Activation of jnk also controls scavenger receptor A I/II (SRA) macrophage phagocytic activity (Ricci, et al., 2004). This report showed that inactivation of jnk trapped SRA on the cell surface and reduced binding and uptake of modified LDL. Whether jnk activation links activity of these 2 scavenger receptors is an intriguing hypothesis which may have important therapeutic implications.

In platelets, CD36 was found to co-precipitate with fyn, lyn and yes, and although CD36 was initially isolated and characterized from platelets, its role remains largely a mystery (Huang, Bolen, Barnwell, Shattil, & Brugge, 1991). However, work in mice and humans underscore the important role for platelets in cardiovascular disease, and thus this remains an unexplored area of CD36 biology.

One can conclude that signaling cascades link CD36 to cellular responses related to innate immunity, scavenger receptor activity, NFκB activation, cytokine and ROS secretion, the initiation of anti-inflammatory and pro-apoptotic pathways, and this has ramifications for the development of atherosclerosis, diabetes, inflammation and the metabolic syndrome, among other pathological states. An important observation from these data is that the consequence of CD36 binding and signaling is apparently both ligand dependent and cell type dependent. Additionally, the proximal event to CD36 binding appears to be, in many cases, activation of a src kinase that leads to MAP kinase activation. Whether CD36 is pro- or anti-inflammatory may also relate to expression of co-receptors. It is then apparent that the outcome of inhibition or activation of CD36 signaling/receptor function is difficult to predict in complex environments.

CD36 Regulation

In monocytes/macrophages, CD36 expression is up regulated by adhesion (Prieto, Eklund, & Patarroyo, 1994, Huh, Lo, Yesner, & Silverstein, 1995), differentiation (Huh, Pearce, Yesner, Schindler, & Silverstein, 1996), certain nuclear hormone receptors and cytokines. For example, CD36 is up regulated in response to the cytokine IL-4 and oxLDL by a common signaling pathway involving protein kinase C and PPAR-γ (Feng, et al., 2000). Transforming growth factor (TGF) β 1/2 can modulate this affect, by activating mitogen-activated protein (MAP) kinase to phosphorylate and inactivate PPAR-γ (Han, Hajjar, Tauras, Feng, Gotto, & Nicholson, 2000). Agonists of PPAR-γ, such as rosiglitazone also increase CD36 expression (Tontonoz, & Nagy, 1999). Zhao et al. (2002) reported that the p38 MAP kinase pathway may also affect PPAR-γ activation and induction of CD36 gene expression. The role of interferon-γ in CD36 regulation remains controversial, although in our hands, we observed no effect (Nakagawa, et al., 1998, Zuckerman, Panousis, Mizrahi, & Evans, 2000, Yesner, Huh, Pearce, & Silverstein, 1996). As mentioned previously, CD36 interaction with apoptotic cells can lead to IL-10 secretion, and Rubic and Lorenz (2006) have reported that IL-10 decreases CD36 expression. This may have anti-atherosclerotic effect as well.

Most statins apparently down regulate CD36 expression, and this may contribute to their efficacy (Pietsch, Erl, & Lorenz, 1996, Fuhrman, Koren, Volkova, Keidar, Hayek, Aviram, 2002, Han, Zhou, Yokoyama, Hajjar, Gotto, & Nicholson, 2004, Puccetti, Sawamura, Pasqui, Pastorelli, Auteri, & Bruni, 2005, Bruni, et al., 2005, Ruiz-Velasco, Dominguez, & Vega, 2004). HIV protease inhibitors up regulate CD36 in male mice and increase atherosclerosis (Dressman, et al., 2003), but have an opposite effect in female mice (Allred, Smart, & Wilson, 2006). In human macrophages, CD36 expression has also been reported up and down regulated by HIV protease inhibitors (Serghides, Nathoo, Walmsley, & Kain, 2002, Munteanu, Zingg, Ricciarelli, & Azzi, 2005) but the reason for the discrepancy has not yet been sorted out. Both up and down regulation of CD36 can have pathological sequellae, as these reports indicate. Thiazolidinediones, a major new class of drugs to treat diabetes, up regulate CD36 in monocytes/macrophages, adipose and muscle (Wilmsen, Ciaraldi, Carter, Reehman, Mudaliar, & Henry, 2003, Kolak, et al., 2006, Hirakata, Tozawa, Imura, & Sugiyama, 2004, Llaverias, et al., 2006), and may therefore contribute to the insulin-sensitizing effects of these drugs as a result of plasma fatty acid clearance, but also potentially to atherosclerosis and obesity in these patients. Interestingly, glucose/insulin appears to increase CD36 expression (Sampson, Davies, Braschi, Ivory, & Hughes, 2003, Griffin, et al., 2001, Chabowski, et al., 2004, Chen, Yang, Loux, Georgeson, & Harmon, 2006), and because CD36 is expressed on tissues important in fatty acid metabolism (heart, skeletal muscle, fat, and in pathological states, liver) this may imply an important role for CD36 in insulin resistance (see later). Regulation of CD36 expression can be mediated both pre- and post- transcription.

Another level of CD36 regulation is via regulation of movement of CD36 from intracellular stores to the plasma membrane. Significant intracellular pools of CD36 have been documented in monocyte/macrophages and muscle (Huh, Pearce, Yesner, Schindler, & Silverstein, 1996, Luiken, et al., 2002). In muscle, increased plasma membrane CD36 expression has been shown to occur after muscle contraction and insulin stimulation (Luiken, et al., 2002, Koonen, et al., 2004, Koonen, Glatz, Bonen, & Luiken, 2005), and analogous to glucose transporter redistribution, may effect energy substrate choice and utilization. In obesity and insulin resistance, there is impairment of this normal recycling, and instead CD36 expression appears locked on the membrane in skeletal muscle (Bonen, et al., 2004, Coort, et al., 2004). The effect of these conditions on localization of CD36 in other tissues/cells has been less well studied, but one may speculate that changes in CD36 localization (and thus function) in cells which are so intimately involved in glucose and fatty acid metabolism may contribute to insulin resistance states and obesity.

Less is known about CD36 regulation in other tissues, although PPAR species are apparently important to regulation in adipocytes, smooth muscle cells and liver (Wilmsen, Ciaraldi, Carter, Reehman, Mudaliar, & Henry, 2003, Motojima, Passilly, Peters, Gonzalez, & Latruffe, 1998, Lim, et al., 2006). In adipose tissue, CD36 expression coincides with differentiation from pre-adipocyte to adipocyte, and capacity to take up fatty acids (Sfeir, Ibrahimi, Amri, Grimaldi, & Abumrad, 1997). In muscle cells, the transcription factor FoxO1, which orchestrates a gene program involved in insulin regulation, impacts CD36 expression, and thus has an important effect on fatty acid uptake by these cells (Bastie, et al., 2005). A recent report has shown that CD36 is a downstream target of the pregnane X receptor in liver, and may be involved in lipid accumulation as a result of activation of this pathway (Zhou, et al., 2006).

CD36 and Insulin Resistance

CD36 KO mice do not show insulin resistance when administered an intraperitoneal bolus of glucose (Febbraio, et al., 1999). In fact, using the euglycemic clamp technique, CD36 KO mice showed slightly higher whole body glucose uptake, oxidation and lower glucose storage at basal conditions when compared with background matched wild type control mice (Goudriaan, et al., 2003). Under hyperinsulinemic conditions, again, CD36 KO mice showed increased whole body glucose uptake and oxidation (Goudriaan, et al., 2003). Interestingly, hepatic glucose production was not inhibited, as one would expect under these conditions (Goudriaan, et al., 2003). Analysis of tissue uptake of labeled glucose showed a significant increase in uptake in cardiac muscle in CD36 KO mice, consistent with our hypothesis that absence of fatty acid uptake by CD36 in heart leads to altered substrate utilization for energy and the fasting hypoglycemia. This hypothesis was more fully tested in an isolated perfused heart system (see later). Thus while absence of CD36 does not lead to diabetes in mice, the mice do have hepatic insulin resistance. In rats, which, unlike mice and humans, express CD36 (males) in liver, a mutation in CD36 was shown to underlie some of the phenotypes of a strain of spontaneously hypertensive rats (SHR) (Aitman, et al., 1999). This is complicated by the fact that several strains of this rat exist and not all have the CD36 mutation (Gotoda, et al., 1999). These rats are hypertensive, insulin resistant and have impaired fatty acid uptake (Pravenec, et al., 1999). The CD36 mutation correlates best with the impaired fatty acid uptake phenotype, which then may affect insulin resistance in this model (especially given the expression of CD36 in liver) (Pravenec, et al., 1999, Collison, et al., 2000, Pravenec, et al., 2001, Hajri, et al., 2001, Zhang, et al., 2003). Indeed, work using CD36 KO mice showed secondary effects to decreased peripheral fatty acid uptake. Goudriaan et al. (2005) showed that the increased plasma fatty acids in CD36 KO mice led to inhibition of lipoprotein lipase activity and delayed metabolism of VLDL, resulting in higher plasma triacylglyceride levels.

In humans, the data with regard to insulin resistance and CD36 has been more difficult to sort out. It is estimated that about 1% of the Japanese population has Type I CD36 deficiency (total), but there have been conflicting reports on insulin resistance in this population (Miyaoka, Kuwasako, Hirano, Nozaki, Yamashita, & Matsuzawa, 2001, Yanai, Chiba, Morimoto, Jamieson, & Matsuno, 2000, Furuhashi, Ura, Nakata, & Shimamoto, 2003, Furuhashi, Ura, Nakata, Tanaka, & Shimamoto, 2004, Kuwasako, et al., 2003, Kajihara, et al., 2001). Polymorphisms in CD36 that are associated with insulin resistance have been identified, but the mechanism by which CD36 impacts insulin resistance remains undefined, and whether these polymorphisms interact with other genetic determinants is not known (Lepretre, et al., 2004a, Lepretre, et al., 2004b, Corpeleijn, et al., 2006). Clearly, fatty acid uptake does differ in muscle in Type I CD36 deficiency (Hwang, et al., 1998, Tanaka, et al., 2001), and this may have differential impact on insulin resistance depending on diet, life style and other genetic factors. The type of genetic mutation (promoter versus coding) may also affect the outcome, as the mutation may affect CD36 expression differentially in different tissues. This aspect of CD36 biology remains one of the most interesting and complicated because of the number of polymorphisms and haplotypes that exist.

The Role of CD36 in Atherogenesis

Endemann et al. (1993) first recognized that CD36 was a receptor for oxLDL, and subsequent work showed that CD36 and scavenger receptor A (SRA), were the principal macrophage receptors responsible for the uptake of modified forms of LDL (Kunjathoor, et al., 2002). Prior to the ability to create murine models of atherosclerosis and scavenger receptor knockouts in the background of these models, one could only speculate as to their role in atherogenesis. Our lab has made significant contributions to the relevance of CD36 to the pathogenesis of atherosclerosis using the apoE KO model. CD36/apoE double KO mice of both genders had significantly less lesion area in the aortic tree after 12 weeks of Western diet feeding (0.15% cholesterol, no cholate) (Febbraio, et al., 2000). This was despite a pro-atherogenic increase in plasma IDL/LDL cholesterol in female mice. Male but not female mice also had significantly reduced lesion area at the level of the aortic sinus on a normal chow diet (Febbraio, et al., 2000). Using a bone marrow transplant approach, we showed that absence of CD36 in hematopoietic cells accounted for the protection observed in the apoE KO model (Febbraio, Guy, & Silverstein, 2004). This study was again using a 12 week Western diet regimen. Mice of both genders lacking CD36 in macrophages alone were profoundly protected against lesion development throughout the aortic tree, and when CD36 was re-introduced into double knock outs, lesion area increased by ∼2-fold. In long term Western diet feeding studies, we found that CD36 continued to play a role in lesion development as a consequence of continued recruitment of macrophages and development of foam cells even in late stage lesions (Guy, Kuchibhotla, Silverstein, & Febbraio, 2006). This was particularly dramatic at 35 weeks of feeding, when aortae from apoE KO mice showed near occlusion with lesion and demonstrated calcification associated with sclerosis. The result of this study was difficult to predict beforehand, given the work of Folkman, et al., who proposed the provocative hypothesis that angiogenesis contributes to the pathogenesis of atherosclerosis and showed that pharmacologic inhibition of angiogenesis led to decreased lesion area, presumably because plaque had inadequate nutrition to grow (Moulton, et al., 2003). Thus, one potential outcome would be that in the absence of the CD36-TSP anti-angiogenic pathway, lesions would actually catch up or grow larger in the CD36/apoE double KO mice. Although our data did not substantiate this hypothesis, it is possible that extensive vessel remodeling, such that vasa vasorum are not the only source of nutrition, played a role.

CD36 is a target gene of PPAR-γ, and activation of PPAR-γ by oxLDL was shown to lead to a feed-forward loop of CD36 expression, uptake of oxLDL and foam cell formation (Tontonoz, & Nagy, L., 1999, Tontonoz, Nagy, Alvarez, Thomazy, & Evans, 1998). Counterbalancing this is an LXR mediated pathway of genes necessary for efflux of cholesterol from macrophages, which can be triggered by oxysterols and the PPAR-γ agonist, rosiglitazone (Chawla, et al., 2001, Chinetti, et al., 2001). There may be situations, therefore, when scavenger receptors are important for inhibition or regression of atherosclerosis, and thus we concur with a recent review by van Berkel et al. that makes the point that the net effect of SRA or CD36 expression in vivo can depend on other factors (2005). For example, treatment with rosiglitazone up regulated CD36 gene and protein expression in male LDLR KO mice, but this was in the context of up regulation of efflux proteins, which apparently enhanced lipoprotein clearance, decreased foam cell formation and reduced atherosclerotic lesion area (Li, Brown, Silvestre, Willson, Palinski, & Glass, 2000). This effect was not observed in female mice for reasons that remain unclear.

In another study, treatment of apoE KO mice with the CD36 ligand and hexarelin derivative, EP 80317, which has no growth hormone releasing properties, decreased atherosclerosis (Marleau, et al., 2005). Examination of the effect of EP 80317 on isolated macrophages showed reduction of uptake of modified LDL, and up-regulation of genes involved in cholesterol/phospholipid efflux, including LXRα, PPAR-γ, ABCA1 and ABCG1 (Marleau, et al., 2005). This was accompanied by decreased total plasma cholesterol suggesting effects both on macrophages and the liver (Marleau, et al., 2005). These effects were not observed in CD36/apoE double KO mice, suggesting a role for CD36.

The view that scavenger receptors (specifically CD36 and SRA) contribute to foam cell formation, particularly in a pro-inflammatory setting, which promotes lipoprotein modifications that enhance their specific recognition by such receptors, was questioned recently in a report by Moore et al. (2005). In that study, CD36/apoE double KO mice were fed a Western diet for 8 weeks and lesions evaluated at both the aortic sinus and throughout the aortic tree. In the case of CD36, in male mice, they reported no significant difference in lesion area at the aortic sinus, and reduced lesion area in the aortic tree, but the difference did not reach statistical significance. They reported disparate results in female mice. While they showed significantly reduced lesion burden throughout the aortic tree, they saw increased lesion area in the aortic sinus. From these data they concluded that absence of scavenger receptors was actually pro-atherogenic, by creating a more pro-inflammatory milieu as a result of lack of uptake of the modified lipid.

Important to this discussion is a recent commentary by Curtiss (2006) in response to a series of papers showing different effects of absence of macrophage ABCG1 in the LDLR KO (Mauldin, et al., 2006, Out, et al., 2006). This commentary suggested that lesion growth at the level of the aortic sinus in high fat/high cholesterol fed mice may not, in fact, be linear, and does not necessarily correlate with lesion burden in the aortic tree. We concur, and actually go further. Whereas in that commentary, size of lesion was compared to time on diet, we would suggest that size of lesion at that location may be a non-linear function of lesion progression. We speculate that perhaps there is a point when lesions not only stop growing linearly or even altogether, as shown in that commentary, but may actually get smaller. How? Like wounds, as lipid and cellular debris are replaced by collagen and other cell types, particularly smooth muscle cells, plaque area may contract, and this may underlie the ability of mice to escape occlusion even after prolonged periods on high fat and cholesterol diets. Because of recognition of the extensive remodeling at the aortic sinus, we have felt that it is more appropriate to measure aortic tree lesion area to assess atherosclerosis extent in Western diet fed mice in our studies. Re-examination of the data of Moore et al. (2005) then shows similar results to what we reported in the aortic tree; the difference in males may manifest more strongly at 12 weeks rather than 8 weeks.

In addition to directly studying the effect of CD36 using CD36 KO mice, a role for CD36 in atherogenesis has been indirectly implied by many other reports. For example, in a study by Hayek et al., (2005) streptozotocin induced diabetic apoE KO mice were assessed for lesion formation. Not surprisingly, there was greater lesion area in diabetic apoE KO compared with non-diabetic controls, and this was statistically significant after 3 months of diabetes. Macrophages isolated from diabetic mice showed increased superoxide content and increased lipid peroxide content. In in vitro studies, macrophages isolated from diabetic apoE KO mice showed increased uptake and degradation of oxLDL and increased accumulation of cholesterol. Using the mouse macrophage cell line, J774, these authors went on to show that increasing glucose content, like oxLDL up regulated CD36 mRNA expression. This suggests a role for CD36 in the pathogenesis of atherosclerosis in type I and type II diabetes that needs further investigation.

Another aspect of CD36 biology that has not been explored and may also be involved in atherogenesis is that of CD36 on platelets. Although our bone marrow study ruled out CD36 expression in many tissues, it did not rule out a potential role for platelets in atherosclerosis and as mentioned previously, despite being the first cell type from which CD36 was characterized, the role of platelet CD36 remains largely undefined.

Other functions of CD36 that may impact cardiovascular disease

Using an isolated perfused heart system in collaboration with the lab of Jason Dyck, we showed that CD36 plays an important role in fuel substrate choice in the heart (Kuang, Febbraio, Wagg, Lopaschuk, & Dyck, 2004). In the absence of CD36, the heart, which normally derives most of its energy from fatty acids, instead relies more heavily on glucose. This confirmed our studies with the radio labeled tracers 125I-BMIPP (a non-metabolizable fatty acid analog), 125I-IPPA (a metabolizable fatty acid analog) and 8-fluorodeoxyglucose (a glucose analog), which were initiated because of the observation that CD36 KO mice have fasting hypoglycemia (Coburn, Knapp, Febbraio, Beets, Silverstein, & Abumrad, 2000). Under normal and high fat conditions, we found that the CD36 KO mouse heart is entirely compensated in terms of ATP and acyl-CoA fatty acids by utilization of glucose (Kuang, Febbraio, Wagg, Lopaschuk, & Dyck, 2004). Even at high work loads, CD36 KO mouse hearts performed as well, if not better than wild type hearts because of full compensation for energy by glucose. Our study results differ from that of Irie et al. (2003) most probably because of the initial condition of the hearts, wild type and CD36 KO, at the time of study. The hearts in our study were shown to be removed in a healthy state from the mice; in the study of Irie et al., wild type hearts failed even in the initial pre-conditioning segment, indicating some technical difficulty. We also found that during ischemia, defined as 18 minutes of Doppler no-flow, CD36 KO mouse hearts were protected and performed better presumably as a result of their reliance on glucose. These results support a large body of literature demonstrating that at the time of myocardial infarction/ischemia, heart muscle converts to glucose metabolism as an energy source. In a recent report, Heather, et al. (2006) found decreased expression of plasma membrane and cytoplasmic fatty acid binding proteins, including CD36 following coronary artery ligation in rats. This correlated with reduced fatty acid oxidation and lipid incorporation.

Work by Cho et al., (2005) using a murine model of middle carotid artery occlusion, showed that ischemic injury led to decreased infarct volume and better neurological outcome in CD36 KO mice. This correlated with decreased expression of damaging ROS, but the complete mechanism remains under investigation, and may also involve differences in platelet and endothelial responses, and angiogenesis. Secretion of ROS and reactive nitrogen species by responding leukocytes and injured cells may contribute to a feed forward loop in terms of generating ligands for CD36 by altering cell membrane and lipoprotein structure, thus providing recognition ligands for macrophages to signal phagocytosis. These ligands may also affect neighboring cell function. Smooth muscle cells, for example, migrate and proliferate in response to oxLDL and ROS (Zhao, Seng, Zhang, & She, 2005, Lyle, & Griendling, 2006). Thus decreased production of ROS and oxidized ligands as a result of absence of CD36 may impact on processes such as neointimal hyperplasia following endothelial injury as a result of less cell injury and apoptosis and reduced smooth muscle cell migration and proliferation. Similarly, there may also be differences in cell death following myocardial infarction/cardiac ischemia.

The relationship of CD36 to macrophage (and global) immune status, either pro- or anti-inflammatory, has been a complex issue. CD36 uptake of apoptotic cells was shown to be one pathway in the suppression of pro-inflammatory cytokines (Voll, Herrmann, Roth, Stach, Kalden, & Girkontaite, 1997), and CD36 is up-regulated in response to IL-4 (Yesner, Huh, Pearce, & Silverstein, 1996), a TH2 cytokine, and down regulated by LPS (Yesner, 1996, Memon, Feingold, Moser, Fuller, & Grunfeld, 1998). Foam cell formation, however, has hallmarks of both a pro-inflammatory (TH1) and innate, scavenger receptor (TH2) phenotype. Whether scavenger receptor uptake of oxLDL promotes or suppresses a pro-inflammatory milieu is an open question, which may impact cardiovascular disease on several levels.

In skeletal muscle, CD36 is important for fatty acid uptake, and its expression is regulated by both the environmental and cellular milieu (Chabowski, Gorski, Calles-Escandon, Tandon, & Bonen, 2006, Chabowski, et al., 2006, Chabowski, et al., 2004, Chabowski, et al., 2005, Benton, Han, Febbraio, Graham, & Bonen, 2006, Cameron-Smith, et al., 2003). Studies in isolated cardiac muscle cells, using a specific CD36 inhibitor, sulfo-N-succinimidyl oleate, also showed that CD36 is likely the major membrane protein involved in fatty acid uptake (Koonen, et al., 2005). The uptake of fatty acids in the periphery affects lipoprotein and glucose metabolism, and thus this indirectly affects cardiovascular health and pathology. Similarly, uptake of fatty acids by adipocyte CD36 also impacts lipoprotein and glucose metabolism. A role for CD36 in cardiovascular health and disease as it relates specifically to these tissues remains to be investigated. A difficulty in studying CD36 is that it is expressed not only in multiple tissues, but multiple cell types within a single tissue. The next generation of study will necessarily rely on transgenic knock in and tissue specific knock out approaches.

Future Prospects

As this review only partially demonstrates, CD36 earns its title as a multifunctional protein. Significant progress has been made in elucidating structure-function properties, ligand interactions, signaling pathways and roles in multiple homeostatic and pathological processes. Still, there is significant work to be done. We need better understanding of how CD36 distinguishes between different ligands, and how this discrimination translates in terms of the signaling pathways activated. Understanding tissue and cell specific roles of CD36, which may be dependent upon associated proteins or targeting to specific membrane domains, are also important to our overall knowledge of how this protein works. Given that several classes of widely used drugs impact CD36 expression, understanding the effect this has on normal and pathological processes becomes imperative.

Figure 2Figure 2
CD36 wears multiple hats. As this review demonstrates functions of CD36 are homeostatic and contribute to normal cellular responses (CD36: The Good). However, in certain contexts, functions of CD36 contribute to pathological states (CD36: The Bad).


It is impossible to mention the work of every investigator who has played a role in our understanding of CD36 biology, but the authors gratefully acknowledge them here for their contributions. We are also indebted to the helpful comments of our colleagues who reviewed this manuscript.


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  • Abumrad NA, el-Maghrabi MR, Amri EZ, Lopez E, Grimaldi PA. 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;268:17665–8. [PubMed]
  • Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996;271:518–20. [PubMed]
  • Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol. 2004;36:961–8. [PMC free article] [PubMed]
  • Aitman TJ, et al. Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nat Genet. 1999;21:76–83. [PubMed]
  • Aitman TJ, et al. Malaria susceptibility and CD36 mutation. Nature. 2000;405:1015–6. [PubMed]
  • Albert ML, et al. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med. 1998;188:1359–68. [PMC free article] [PubMed]
  • Allen MH, Barker JN, MacDonald DM. Keratinocyte expression of CD36 antigen in benign and malignant epidermal cell-derived tumours. J Cutan Pathol. 1991;18:198–203. [PubMed]
  • Allred KF, Smart EJ, Wilson ME. Estrogen receptor-alpha mediates gender differences in atherosclerosis induced by HIV protease inhibitors. J Biol Chem. 2006;281:1419–25. [PMC free article] [PubMed]
  • Armesilla AL, Calvo D, Vega MA. Structural and functional characterization of the human CD36 gene promoter: identification of a proximal PEBP2/CBF site. J Biol Chem. 1996;271:7781–7. [PubMed]
  • Asch AS, et al. Analysis of CD36 binding domains: ligand specificity controlled by dephosphorylation of an ectodomain. Science. 1993;262:1436–40. [PubMed]
  • Baillie AGS, Coburn CT, Abumrad NA. Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog. J Membr Biol. 1996;153:75–81. [PubMed]
  • Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci. 2003;23:2665–74. [PubMed]
  • Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004;63:582–92. [PubMed]
  • Bastie CC, et al. FoxO1 stimulates fatty acid uptake and oxidation in muscle cells through CD36-dependent and -independent mechanisms. J Biol Chem. 2005;280:14222–9. [PubMed]
  • Benton CR, et al. Differential effects of contraction and PPAR agonists on the expression of fatty acid transporters in rat skeletal muscle. J Physiol. 2006;573:199–210. [PMC free article] [PubMed]
  • Benton CR, Han XX, Febbraio M, Graham TE, Bonen A. Inverse relationship between PGC-1alpha protein expression and triacylglycerol accumulation in rodent skeletal muscle. J Appl Physiol. 2006;100:377–83. [PubMed]
  • Bodart V, et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res. 2002;90:844–9. [PubMed]
  • Bolin RB, Medina F, Cheney BA. Glycoprotein changes in fresh vs. room temperature-stored platelets and their buoyant density cohorts. J Lab Clin Med. 1981;98:500–10. [PubMed]
  • Bonen A, et al. Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36. Faseb J. 2004;18:1144–1146. [PubMed]
  • Bradshaw EL, et al. Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C. Am J Physiol Cell Physiol. 2006;291:C1271–8. [PubMed]
  • Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–1625. [PubMed]
  • Bruni F, et al. Different effect of statins on platelet oxidized-LDL receptor (CD36 and LOX-1) expression in hypercholesterolemic subjects. Clin Appl Thromb Hemost. 2005;11:417–28. [PubMed]
  • Calvo D, Gomez-Coronado D, Suarez Y, Lasuncion MA, Vega MA. Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. J Lipid Res. 1998;39:777–88. [PubMed]
  • Cameron-Smith D, et al. A short-term, high-fat diet up-regulates lipid metabolism and gene expression in human skeletal muscle. Am J Clin Nutr. 2003;77:313–8. [PubMed]
  • Chabowski A, et al. Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm. Am J Physiol Endocrinol Metab. 2004;287:E781–9. [PubMed]
  • Chabowski A, et al. The subcellular compartmentation of fatty acid transporters is regulated differently by insulin and by AICAR. FEBS Lett. 2005;579:2428–32. [PubMed]
  • Chabowski A, et al. Prolonged AMPK activation increases the expression of fatty acid transporters in cardiac myocytes and perfused hearts. Mol Cell Biochem. 2006;288:201–12. [PubMed]
  • Chabowski A, Gorski J, Calles-Escandon J, Tandon NN, Bonen A. Hypoxia-induced fatty acid transporter translocation increases fatty acid transport and contributes to lipid accumulation in the heart. FEBS Lett. 2006;580:3617–23. [PubMed]
  • Chawla A, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001;7:161–71. [PubMed]
  • Chen CH, et al. Inhibitory effects of hypercholesterolemia and ox-LDL on angiogenesis-like endothelial growth in rabbit aortic explants. Essential role of basic fibroblast growth factor. Arterioscler Thromb Vasc Biol. 1997;17:1303–12. [PubMed]
  • Chen M, Yang Y. Braunstein E, Georgeson KE, Harmon CM, editors. Gut expression and regulation of FAT/CD36: possible role in fatty acid transport in rat enterocytes. Am J Physiol Endocrinol Metab. 2001;281:E916–23. [PubMed]
  • Chen M, Yang YK, Loux TJ, Georgeson KE, Harmon CM. The role of hyperglycemia in FAT/CD36 expression and function. Pediatr Surg Int. 2006;22:647–54. [PubMed]
  • Chinetti G, et al. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med. 2001;7:53–8. [PubMed]
  • Cho S, et al. The class B scavenger receptor CD36 mediates free radical production and tissue injury in cerebral ischemia. J Neurosci. 2005;25:2504–12. [PubMed]
  • Clezardin P, Frappart L, Clerget M, Pechoux C, Delmas PD. Expression of thrombospondin (TSP1) and its receptors (CD36 and CD51) in normal, hyperplastic, and neoplastic human breast. Cancer Res. 1993;53:1421–30. [PubMed]
  • Coburn CT, Knapp FF, Jr., Febbraio M, Beets AL, Silverstein RL, Abumrad NA. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem. 2000;275:32523–9. [PubMed]
  • Collison M, et al. Cd36 and molecular mechanisms of insulin resistance in the stroke-prone spontaneously hypertensive rat. Diabetes. 2000;49:2222–6. [PubMed]
  • Coort SL, et al. Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. Diabetes. 2004;53:1655–1663. [PubMed]
  • Corpeleijn E, et al. Direct association of a promoter polymorphism in the CD36/FAT fatty acid transporter gene with Type 2 diabetes mellitus and insulin resistance. Diabet Med. 2006;23:907–11. [PubMed]
  • Crombie R, Silverstein R. Lysosomal integral membrane protein II binds thrombospondin-1. Structure-function homology with the cell adhesion molecule CD36 defines a conserved recognition motif. J Biol Chem. 1998;273:4855–63. [PubMed]
  • Curtiss LK. Is two out of three enough for ABCG1? Arterioscler Thromb Vasc Biol. 2006;26:2175–7. [PubMed]
  • Daviet L, Buckland R, Puente Navazo MD, McGregor JL. Identification of an immunodominant functional domain on human CD36 antigen using human-mouse chimaeric proteins and homologue-replacement mutagenesis. Biochem J. 1995;305:221–4. [PMC free article] [PubMed]
  • Dawson DW, et al. Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat. Mol Pharmacol. 1999;55:332–8. [PubMed]
  • Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck NP. CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells. J Cell Biol. 1997;138:707–17. [PMC free article] [PubMed]
  • Demers A, et al. Identification of the growth hormone-releasing peptide binding site in CD36: a photoaffinity cross-linking study. Biochem J. 2004;382:417–24. [PMC free article] [PubMed]
  • de Oliveira Silva C, Delbosc S, Arais C, Monnier L, Cristol JP, Pares-Herbute N. Modulation of CD36 protein expression by AGEs and insulin in aortic VSMCs from diabetic and non-diabetic rats. Nutr Metab Cardiovasc Dis. 2006 Nov 24; epub. [PubMed]
  • Dorahy DJ, Lincz LF. Meldrum CJ, Burns GF, editors. Biochemical isolation of a membrane microdomain from resting platelets highly enriched in the plasma membrane glycoprotein CD36. Biochem J. 1996;319:67–72. [PMC free article] [PubMed]
  • Dressman J, et al. HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages. J Clin Invest. 2003;111:389–97. [PMC free article] [PubMed]
  • El Khoury JB, et al. CD36 mediates the innate host response to beta-amyloid. J Exp Med. 2003;197:1657–66. [PMC free article] [PubMed]
  • Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993;268:11811–6. [PubMed]
  • Englyst NA, Taube JM, Aitman TJ, Baglin TP, Byrne CD. A novel role for CD36 in VLDL-enhanced platelet activation. Diabetes. 2003;52:1248–55. [PubMed]
  • Eyre NS, Cleland LG, Tandon NN, Mayrhofer G. Involvement of the C-terminal cytoplasmic domain in the plasma membrane localization of FAT/CD36 and its ability to mediate long-chain fatty acid uptake. J Lipid Res. 2007;48:528–42. [PubMed]
  • Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ. 1998;5:551–62. [PubMed]
  • Farhangkhoee H, Khan ZA, Barbin Y, Chakrabarti S. Glucose-induced up-regulation of CD36 mediates oxidative stress and microvascular endothelial cell dysfunction. Diabetologia. 2005;48:1401–10. [PubMed]
  • Febbraio M, et al. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J Biol Chem. 1999;274:19055–62. [PubMed]
  • Febbraio M, et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest. 2000;105:1049–56. [PMC free article] [PubMed]
  • Febbraio M, Guy E, Silverstein RL. Stem cell transplantation reveals that absence of macrophage CD36 is protective against atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:2333–8. [PubMed]
  • Feng J, et al. Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma. J Lipid Res. 2000;41:688–96. [PubMed]
  • Fernandez-Ruiz E, Armesilla AL, Sanchez-Madrid F, Vega MA. Gene encoding the collagen type I and thrombospondin receptor CD36 is located on chromosome 7q11.2. Genomics. 1993;17:759–61. [PubMed]
  • Forbes JM, Soldatos G, Thomas MC. Below the radar: advanced glycation end products that detour “around the side”. Is HbA1c not an accurate enough predictor of long term progression and glycaemic control in diabetes? Clin Biochem Rev. 2005;26:123–34. [PMC free article] [PubMed]
  • Franc NC, Dimarcq JL, Lagueux M, Hoffmann J, Ezekowitz RA. Croquemort, a novel Drosophila hemocyte/macrophage receptor that recognizes apoptotic cells. Immunity. 1996;4:431–43. [PubMed]
  • Franc NC, Heitzler P, Ezekowitz RA, White K. Requirement for croquemort in phagocytosis of apoptotic cells in Drosophila. Science. 1999;284:1991–4. [PubMed]
  • Frank PG, Lee H, Park DS, Tandon NN, Scherer PE, Lisanti MP. Genetic ablation of caveolin-1 confers protection against atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:98–105. [PubMed]
  • Franke-Fayard B, et al. Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration. Proc Natl Acad Sci U S A. 2005;102:11468–73. [PMC free article] [PubMed]
  • Fuhrman B, Koren L, Volkova N, Keidar S, Hayek T, Aviram M. Atorvastatin therapy in hypercholesterolemic patients suppresses cellular uptake of oxidized-LDL by differentiating monocytes. Atherosclerosis. 2002;164:179–85. [PubMed]
  • Furuhashi M, Ura N, Nakata T, Tanaka T, Shimamoto K. Genotype in human CD36 deficiency and diabetes mellitus. Diabet Med. 2004;21:952–3. [PubMed]
  • Furuhashi M, Ura N, Nakata T, Shimamoto K. Insulin sensitivity and lipid metabolism in human CD36 deficiency. Diabetes Care. 2003;26:471–4. [PubMed]
  • Gamp AC, et al. LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice. Hum Mol Genet. 2003;12:631–46. [PubMed]
  • Gelhaus A, Scheding A, Browne E, Burchard GD, Horstmann RD. Variability of the CD36 gene in West Africa. Hum Mutat. 2001;18:444–50. [PubMed]
  • Gietema JA, et al. A phase I study assessing the safety and pharmacokinetics of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with gemcitabine and cisplatin in patients with solid tumors. Ann Oncol. 2006;17:1320–1327. [PubMed]
  • Glatz JF, Bonen A, Luiken JJ. Exercise and insulin increase muscle fatty acid uptake by recruiting putative fatty acid transporters to the sarcolemma. Curr Opin Clin Nutr Metab Care. 2002;5:365–370. [PubMed]
  • Gordon S. Pattern recognition receptors: doubling up for the innate immune response. Cell. 2002;111:927–30. [PubMed]
  • Gotoda T, et al. Absence of Cd36 mutation in the original spontaneously hypertensive rats with insulin resistance. Nat Genet. 1999;22:226–8. [PubMed]
  • Goudriaan JR, et al. CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice. J Lipid Res. 2003;44:2270–7. [PubMed]
  • Goudriaan JR, et al. CD36 deficiency in mice impairs lipoprotein lipase-mediated triglyceride clearance. J Lipid Res. 2005;46:2175–81. [PubMed]
  • Greenberg ME, Sun M, Zhang R, Febbraio M, Silverstein R, Hazen SL. Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. J Exp Med. 2006;203:2613–25. [PMC free article] [PubMed]
  • Griffin E, et al. A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation. Nat Med. 2001;7:840–6. [PubMed]
  • Gruarin P, Thorne RF, Dorahy DJ, Burns GF, Sitia R, Alessio M. CD36 is a ditopic glycoprotein with the N-terminal domain implicated in intracellular transport. Biochem Biophys Res Commun. 2000;275:446–54. [PubMed]
  • Guy E, Kuchibhotla S, Silverstein R, Febbraio M. Continued inhibition of atherosclerotic lesion development in long term Western diet fed CD36 KO/apoE KO mice. Atherosclerosis. 2006 Aug 16; epub. [PubMed]
  • Hajri T, et al. Defective fatty acid uptake in the spontaneously hypertensive rat is a primary determinant of altered glucose metabolism, hyperinsulinemia, and myocardial hypertrophy. J Biol Chem. 2001;276:23661–6. [PubMed]
  • Han J, Hajjar DP, Tauras JM, Feng J, Gotto AM, Jr., Nicholson AC. Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-gamma. J Biol Chem. 2000;275:1241–6. [PubMed]
  • Han J, Zhou X, Yokoyama T, Hajjar DP, Gotto AM, Jr., Nicholson AC. Pitavastatin downregulates expression of the macrophage type B scavenger receptor, CD36. Circulation. 2004;109:790–6. [PubMed]
  • Hashimoto M, et al. Not lipoteichoic acid but lipoproteins appear to be the dominant immunobiologically active compounds in Staphylococcus aureus. J Immunol. 2006;177:3162–9. [PubMed]
  • Hatmi M, Gavaret JM, Elalamy I, Vargaftig BB, Jacquemin C. Evidence for cAMP-dependent platelet ectoprotein kinase activity that phosphorylates platelet glycoprotein IV (CD36) J Biol Chem. 1996;271:24776–80. [PubMed]
  • Hayek T, et al. Macrophage-foam cell formation in streptozotocin-induced diabetic mice: stimulatory effect of glucose. Atherosclerosis. 2005;183:25–33. [PubMed]
  • Heather LC, et al. Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovasc Res. 2006;72:430–437. [PubMed]
  • Henry PD. Hypercholesterolemia and angiogenesis. Am J Cardiol. 1993;72:61C–64C. [PubMed]
  • Hirakata M, Tozawa R, Imura Y, Sugiyama Y. Comparison of the effects of pioglitazone and rosiglitazone on macrophage foam cell formation. Biochem Biophys Res Commun. 2004;323:782–8. [PubMed]
  • Ho M, et al. Ectophosphorylation of CD36 regulates cytoadherence of Plasmodium falciparum to microvascular endothelium under flow conditions. Infect Immun. 2005;73:8179–87. [PMC free article] [PubMed]
  • Hoebe K, et al. CD36 is a sensor of diacylglycerides. Nature. 2005;433:523–7. [PubMed]
  • Huang H, et al. Peroxisome proliferator-activated receptor gamma ligands improve the antitumor efficacy of thrombospondin peptide ABT510. Mol Cancer Res. 2004;2:541–50. [PubMed]
  • Huang MM, Bolen JB, Barnwell JW, Shattil SJ, Brugge JS. Membrane glycoprotein IV (CD36) is physically associated with the Fyn, Lyn, and Yes protein-tyrosine kinases in human platelets. Proc Natl Acad Sci U S A. 1991;88:7844–8. [PMC free article] [PubMed]
  • Huh HY, Lo SK, Yesner LM, Silverstein RL. CD36 induction on human monocytes upon adhesion to tumor necrosis factor-activated endothelial cells. J Biol Chem. 1995;270:6267–71. [PubMed]
  • Huh HY, Pearce SF, Yesner LM, Schindler JL, Silverstein RL. Regulated expression of CD36 during monocyte-to-macrophage differentiation: potential role of CD36 in foam cell formation. Blood. 1996;87:2020–8. [PubMed]
  • Husemann J, Loike JD, Anankov R, Febbraio M, Silverstein SC. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia. 2002;40:195–205. [PubMed]
  • Hwang EH, et al. Absent myocardial iodine-123-BMIPP uptake and platelet/monocyte CD36 deficiency. J Nucl Med. 1998;39:1681–4. [PubMed]
  • Imanishi T, Hano T, Matsuo Y, Nishio I. Oxidized low-density lipoprotein inhibits vascular endothelial growth factor-induced endothelial progenitor cell differentiation. Clin Exp Pharmacol Physiol. 2003;30:665–70. [PubMed]
  • Irie H, et al. Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids. Proc Natl Acad Sci U S A. 2003;100:6819–24. [PMC free article] [PubMed]
  • Iruela-Arispe ML, Lombardo M, Krutzsch HC, Lawler J, Roberts DD. Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats. Circulation. 1999;100:1423–31. [PubMed]
  • Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med. 2000;6:41–8. [PubMed]
  • Jochen A, Hays J. Purification of the major substrate for palmitoylation in rat adipocytes: N-terminal homology with CD36 and evidence for cell surface acylation. J Lipid Res. 1993;34:1783–92. [PubMed]
  • Kajihara S, et al. Association of the Pro90Ser CD36 mutation with elevated free fatty acid concentrations but not with insulin resistance syndrome in Japanese. Clin Chim Acta. 2001;314:125–30. [PubMed]
  • Kieffer N, Nurden AT, Hasitz M, Titeux M, Breton-Gorius J. Identification of platelet membrane thrombospondin binding molecules using an anti-thrombospondin antibody. Biochim Biophys Acta. 1988;967:408–15. [PubMed]
  • Kincer JF, et al. Hypercholesterolemia promotes a CD36-dependent and endothelial nitric-oxide synthase-mediated vascular dysfunction. J Biol Chem. 2002;277:23525–33. [PubMed]
  • Kolak M, et al. Effects of chronic rosiglitazone therapy on gene expression in human adipose tissue in vivo in patients with type 2 diabetes. J Clin Endocrinol Metab. 2007;92:720–4. [PubMed]
  • Koonen DP, et al. Different mechanisms can alter fatty acid transport when muscle contractile activity is chronically altered. Am J Physiol Endocrinol Metab. 2004;286:E1042–1049. [PubMed]
  • Koonen DP, Glatz JF, Bonen A, Luiken JJ. Long-chain fatty acid uptake and FAT/CD36 translocation in heart and skeletal muscle. Biochim Biophys Acta. 2005;1736:163–80. [PubMed]
  • Krieger M. The other side of scavenger receptors: pattern recognition for host defense. Curr Opin Lipidol. 1997;8:275–80. [PubMed]
  • Kuang M, Febbraio M, Wagg C, Lopaschuk GD, Dyck JR. Fatty acid translocase/CD36 deficiency does not energetically or functionally compromise hearts before or after ischemia. Circulation. 2004;109:1550–7. [PubMed]
  • Kunjathoor VV, et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem. 2002;277:49982–8. [PubMed]
  • Kuwasako T, et al. Lipoprotein Abnormalities in Human Genetic CD36 Deficiency Associated With Insulin Resistance and Abnormal Fatty Acid Metabolism. Diabetes Care. 2003;26:1647–8. [PubMed]
  • Kwok CF, Juan CC, Ho LT. Endothelin-1 decreases CD36 protein expression in vascular smooth muscle cells. Am J Physiol Endocrinol Metab. 2007;292:E648–52. [PubMed]
  • Laugerette F, et al. CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions. J Clin Invest. 2005;115:3177–84. [PMC free article] [PubMed]
  • Lee K, et al. CD36 deficiency is frequent and can cause platelet immunization in Africans. Transfusion. 1999;39:873–9. [PubMed]
  • Lepretre F, et al. Genetic study of the CD36 gene in a French diabetic population. Diabetes Metab. 2004a;30:459–63. [PubMed]
  • Lepretre F, et al. A CD36 nonsense mutation associated with insulin resistance and familial type 2 diabetes. Hum Mutat. 2004b;24:104. [PubMed]
  • Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2000;106:523–31. [PMC free article] [PubMed]
  • Lim HJ, et al. PPAR gamma activation induces CD36 expression and stimulates foam cell like changes in rVSMCs. Prostaglandins Other Lipid Mediat. 2006;80:165–74. [PubMed]
  • Llaverias G, et al. Effects of rosiglitazone and atorvastatin on the expression of genes that control cholesterol homeostasis in differentiating monocytes. Biochem Pharmacol. 2006;71:605–14. [PubMed]
  • Lucas M, et al. Requirements for apoptotic cell contact in regulation of macrophage responses. J Immunol. 2006;177:4047–54. [PubMed]
  • Luiken JJ, et al. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36. Diabetes. 2002;51:3113–3119. [PubMed]
  • Lyle AN, Griendling KK. Modulation of vascular smooth muscle signaling by reactive oxygen species. Physiology. 2006;21:269–80. [PubMed]
  • Ma X, et al. A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians. Hum Mol Genet. 2004;13:2197–205. [PubMed]
  • Malaud E, Hourton D, Giroux LM, Ninio E, Buckland R, McGregor JL. The terminal six amino-acids of the carboxy cytoplasmic tail of CD36 contain a functional domain implicated in the binding and capture of oxidized low-density lipoprotein. Biochem J. 2002;364:507–15. [PMC free article] [PubMed]
  • Marleau S, et al. EP 80317, a ligand of the CD36 scavenger receptor, protects apolipoprotein E-deficient mice from developing atherosclerotic lesions. Faseb J. 2005;19:1869–71. [PubMed]
  • Mauldin JP, et al. Reduction in ABCG1 in Type 2 diabetic mice increases macrophage foam cell formation. J Biol Chem. 2006;281:21216–24. [PubMed]
  • Medeiros LA, et al. Fibrillar amyloid protein present in atheroma activates CD36 signal transduction. J Biol Chem. 2004;279:10643–8. [PubMed]
  • Memon RA, Feingold KR, Moser AH, Fuller J, Grunfeld C. Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines. Am J Physiol. 1998;274:E210–7. [PubMed]
  • Miao WM, Seng WL, Duquette M, Lawler P, Laus C, Lawler J. Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms. Cancer Res. 2001;61:7830–9. [PubMed]
  • Miyaoka K, Kuwasako T, Hirano K, Nozaki S, Yamashita S, Matsuzawa Y. CD36 deficiency associated with insulin resistance. Lancet. 2001;357:686–7. [PubMed]
  • Moore KJ, et al. A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid. J Biol Chem. 2002;277:47373–9. [PubMed]
  • Moore KJ, et al. Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J Clin Invest. 2005;115:2192–201. [PMC free article] [PubMed]
  • Motojima K, Passilly P, Peters JM, Gonzalez FJ, Latruffe N. Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem. 1998;273:16710–4. [PubMed]
  • Moulton KS, et al. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A. 2003;100:4736–41. [PMC free article] [PubMed]
  • Munteanu A, Zingg JM, Ricciarelli R, Azzi A. CD36 overexpression in ritonavir-treated THP-1 cells is reversed by alpha-tocopherol. Free Radic Biol Med. 2005;38:1047–56. [PubMed]
  • Mwaikambo BR, Sennlaub F, Ong H, Chemtob S, Hardy P. Activation of CD36 inhibits and induces regression of inflammatory corneal neovascularization. Invest Ophthalmol Vis Sci. 2006;47:4356–64. [PubMed]
  • Nakagawa T, et al. Oxidized LDL increases and interferon-gamma decreases expression of CD36 in human monocyte-derived macrophages. Arterioscler Thromb Vasc Biol. 1998;18:1350–7. [PubMed]
  • Navazo MD, Daviet L, Savill J, Ren Y, Leung LL, McGregor JL. Identification of a domain (155−183) on CD36 implicated in the phagocytosis of apoptotic neutrophils. J Biol Chem. 1996;271:15381–5. [PubMed]
  • NCBI http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=948 SNP database.
  • Ohgami N, et al. Cd36, a member of the class b scavenger receptor family, as a receptor for advanced glycation end products. J Biol Chem. 2001;276:3195–202. [PubMed]
  • Oquendo P, Hundt E, Lawler J, Seed B. CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes. Cell. 1989;58:95–101. [PubMed]
  • Out R, et al. Macrophage ABCG1 deletion disrupts lipid homeostasis in alveolar macrophages and moderately influences atherosclerotic lesion development in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2006;26:2295–300. [PubMed]
  • Pearce SF, Roy P, Nicholson AC, Hajjar DP, Febbraio M, Silverstein RL. Recombinant glutathione S-transferase/CD36 fusion proteins define an oxidized low density lipoprotein-binding domain. J Biol Chem. 1998;273:34875–81. [PubMed]
  • Pearce SF, Wu J, Silverstein RL. Recombinant GST/CD36 fusion proteins define a thrombospondin binding domain. Evidence for a single calcium-dependent binding site on CD36. J Biol Chem. 1995;270:2981–6. [PubMed]
  • Pietsch A, Erl W, Lorenz RL. Lovastatin reduces expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells. Biochem Pharmacol. 1996;52:433–9. [PubMed]
  • Pittoni V, Valesini G. The clearance of apoptotic cells: implications for autoimmunity. Autoimmun Rev. 2002;1:154–61. [PubMed]
  • Platt N, Gordon S. Scavenger receptors: diverse activities and promiscuous binding of polyanionic ligands. Chem Biol. 1998;5:R193–203. [PubMed]
  • Podrez EA, et al. Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J Clin Invest. 2000;105:1095–108. [PMC free article] [PubMed]
  • Podrez EA, et al. Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36. J Biol Chem. 2002a;277:38503–16. [PubMed]
  • Podrez EA, et al. A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions. J Biol Chem. 2002b;277:38517–23. [PubMed]
  • Pohl J, Ring A, Korkmaz U, Ehehalt R, Stremmel W. FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts. Mol Biol Cell. 2005;16:24–31. [PMC free article] [PubMed]
  • Pravenec M, et al. Genetics of Cd36 and the clustering of multiple cardiovascular risk factors in spontaneous hypertension. J Clin Invest. 1999;103:1651–7. [PMC free article] [PubMed]
  • Pravenec M, et al. Transgenic rescue of defective Cd36 ameliorates insulin resistance in spontaneously hypertensive rats. Nat Genet. 2001;27:156–8. [PubMed]
  • Prieto J, Eklund A, Patarroyo M. Regulated expression of integrins and other adhesion molecules during differentiation of monocytes into macrophages. Cell Immunol. 1994;156:191–211. [PubMed]
  • Primo L, et al. Identification of CD36 molecular features required for its in vitro angiostatic activity. Faseb J. 2005;19:1713–5. [PubMed]
  • Puccetti L, Sawamura T, Pasqui AL, Pastorelli M, Auteri A, Bruni F. Atorvastatin reduces platelet-oxidized-LDL receptor expression in hypercholesterolaemic patients. Eur J Clin Invest. 2005;35:47–51. [PubMed]
  • Puente Navazo MD, Daviet L, Ninio E, McGregor JL. Identification on human CD36 of a domain (155−183) implicated in binding oxidized low-density lipoproteins (Ox-LDL) Arterioscler Thromb Vasc Biol. 1996;16:1033–9. [PubMed]
  • Rahaman SO, Lennon DJ, Febbraio M, Podrez EA, Hazen SL, Silverstein RL. A CD36-dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab. 2006;4:211–21. [PMC free article] [PubMed]
  • Ricci R, et al. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science. 2004;306:1558–61. [PubMed]
  • Ring A, Le Lay S, Pohl J, Verkade P, Stremmel W. Caveolin-1 is required for fatty acid translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic fibroblasts. Biochim Biophys Acta. 2006;1761:416–23. [PubMed]
  • Rouabhia M, Jobin N, Doucet R,, Jr., Bergeron J, Auger FA. CD36(+)-dendritic epidermal cells: a putative actor in the cutaneous immune system. Cell Transplant. 1994;3:529–36. [PubMed]
  • Rubic T, Lorenz RL. Downregulated CD36 and oxLDL uptake and stimulated ABCA1/G1 and cholesterol efflux as anti-atherosclerotic mechanisms of interleukin-10. Cardiovasc Res. 2006;69:527–35. [PubMed]
  • Ruiz-Velasco N, Dominguez A, Vega MA. Statins upregulate CD36 expression in human monocytes, an effect strengthened when combined with PPAR-gamma ligands Putative contribution of Rho GTPases in statin-induced CD36 expression. Biochem Pharmacol. 2004;67:303–13. [PubMed]
  • Rusk A, McKeegan E, Haviv F, Majest S, Henkin J, Khanna C. Preclinical evaluation of antiangiogenic thrombospondin-1 peptide mimetics, ABT-526 and ABT-510, in companion dogs with naturally occurring cancers. Clin Cancer Res. 2006;12:7444–7455. [PubMed]
  • Ryeom SW, Silverstein RL, Scotto A, Sparrow JR. Binding of anionic phospholipids to retinal pigment epithelium may be mediated by the scavenger receptor CD36. J Biol Chem. 1996;271:20536–9. [PubMed]
  • Ryeom SW, Sparrow JR, Silverstein RL. CD36 participates in the phagocytosis of rod outer segments by retinal pigment epithelium. J Cell Sci. 1996;109:387–95. [PubMed]
  • Sampson MJ, Davies IR, Braschi S, Ivory K, Hughes DA. Increased expression of a scavenger receptor (CD36) in monocytes from subjects with Type 2 diabetes. Atherosclerosis. 2003;167:129–34. [PubMed]
  • Savill J, Hogg N, Ren Y, Haslett C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J Clin Invest. 1992;90:1513–22. [PMC free article] [PubMed]
  • Serghides L, Nathoo S, Walmsley S, Kain KC. CD36 deficiency induced by antiretroviral therapy. Aids. 2002;16:353–8. [PubMed]
  • Serghides L, Smith TG, Patel SN, Kain KC. CD36 and malaria: friends or foes? Trends Parasitol. 2003;19:461–9. [PubMed]
  • Sfeir Z, Ibrahimi A, Amri E, Grimaldi P, Abumrad N. Regulation of FAT/CD36 gene expression: further evidence in support of a role of the protein in fatty acid binding/transport. Prostaglandins Leukot Essent Fatty Acids. 1997;57:17–21. [PubMed]
  • Simantov R, Febbraio M, Silverstein RL. The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein. Matrix Biol. 2005;24:27–34. [PubMed]
  • Spitsberg VL, Matitashvili E, Gorewit RC. Association and coexpression of fatty-acid-binding protein and glycoprotein CD36 in the bovine mammary gland. Eur J Biochem. 1995;230:872–878. [PubMed]
  • Stewart CR, et al. Oxidation of Low-Density Lipoproteins Induces Amyloid-like Structures That Are Recognized by Macrophages. Biochemistry. 2005;44:9108–9116. [PubMed]
  • Stuart LM, et al. Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain. J Cell Biol. 2005;170:477–85. [PMC free article] [PubMed]
  • Sugihara K, Sugihara T, Mohandas N, Hebbel RP. Thrombospondin mediates adherence of CD36+ sickle reticulocytes to endothelial cells. Blood. 1992;80:2634–42. [PubMed]
  • Sun M, et al. Light-induced oxidation of photoreceptor outer segment phospholipids generates ligands for CD36-mediated phagocytosis by retinal pigment epithelium: a potential mechanism for modulating outer segment phagocytosis under oxidant stress conditions. J Biol Chem. 2006;281:4222–30. [PMC free article] [PubMed]
  • Susztak K, Ciccone E, McCue P, Sharma K, Bottinger EP. Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy. PLoS Med. 2005;2:e45. [PMC free article] [PubMed]
  • Swerlick RA, Lee KH, Wick TM, Lawley TJ. Human dermal microvascular endothelial but not human umbilical vein endothelial cells express CD36 in vivo and in vitro. J Immunol. 1992;148:78–83. [PubMed]
  • Tanaka T, et al. Defect in human myocardial long-chain fatty acid uptake is caused by FAT/CD36 mutations. J Lipid Res. 2001;42:751–9. [PubMed]
  • Tandon NN, Lipsky RH, Burgess WH, Jamieson GA. Isolation and characterization of platelet glycoprotein IV (CD36) J Biol Chem. 1989;264:7570–5. [PubMed]
  • Tao N, Wagner SJ, Lublin DM. CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails. J Biol Chem. 1996;271:22315–20. [PubMed]
  • Taylor KT, Tang Y, Sobieski DA, Lipsky RH. Characterization of two alternatively spliced 5′-untranslated exons of the human CD36 gene in different cell types. Gene. 1993;133:205–12. [PubMed]
  • Thorne RF, Law EG, Elith CA, Ralston KJ, Bates RC, Burns GF. The association between CD36 and Lyn protein tyrosine kinase is mediated by lipid. Biochem Biophys Res Commun. 2006;351:51–56. [PubMed]
  • Tirziu D, et al. Delayed arteriogenesis in hypercholesterolemic mice. Circulation. 2005;112:2501–9. [PubMed]
  • Tontonoz P, Nagy L. Regulation of macrophage gene expression by peroxisome-proliferator-activated receptor gamma: implications for cardiovascular disease. Curr Opin Lipidol. 1999;10:485–90. [PubMed]
  • Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell. 1998;93:241–52. [PubMed]
  • Triantafilou M, et al. Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting. J Biol Chem. 2006;281:31002–11. [PubMed]
  • van Berkel TJ, Out R, Hoekstra M, Kuiper J, Biessen E, van Eck M. Scavenger receptors: friend or foe in atherosclerosis? Curr Opin Lipidol. 2005;16:525–35. [PubMed]
  • Van Nieuwenhoven FA, et al. 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;207:747–52. [PubMed]
  • van Weel V, et al. Hypercholesterolemia reduces collateral artery growth more dominantly than hyperglycemia or insulin resistance in mice. Arterioscler Thromb Vasc Biol. 2006;26:1383–90. [PubMed]
  • Vistisen B, Roepstorff K, Roepstorff C, Bonen A, van Deurs B, Kiens B. Sarcolemmal FAT/CD36 in human skeletal muscle colocalizes with caveolin-3 and is more abundant in type 1 than in type 2 fibers. J Lipid Res. 2004;45:603–9. [PubMed]
  • Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature. 1997;390:350–1. [PubMed]
  • Vosper H, et al. The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages. J Biol Chem. 2001;276:44258–65. [PubMed]
  • Watanabe K, et al. Myocardial CD36 expression and fatty acid accumulation in patients with type I and II CD36 deficiency. Ann Nucl Med. 1998;12:261–6. [PubMed]
  • Wilkinson B, Koenigsknecht-Talboo J, Grommes C, Lee CY, Landreth G. Fibrillar beta-Amyloid-stimulated Intracellular Signaling Cascades Require Vav for Induction of Respiratory Burst and Phagocytosis in Monocytes and Microglia. J Biol Chem. 2006;281:20842–50. [PubMed]
  • Wilmsen HM, Ciaraldi TP, Carter L, Reehman N, Mudaliar SR, Henry RR. Thiazolidinediones upregulate impaired fatty acid uptake in skeletal muscle of type 2 diabetic subjects. Am J Physiol Endocrinol Metab. 2003;285:E354–62. [PubMed]
  • Wyler B, Daviet L, Bortkiewicz H, Bordet JC, McGregor JL. Cloning of the cDNA encoding human platelet CD36: comparison to PCR amplified fragments of monocyte, endothelial and HEL cells. Thromb Haemost. 1993;70:500–5. [PubMed]
  • XenneX, Inc. www.genecards.org/cgi-bin/carddisp.pl?gene=CD36 GeneCards.
  • Yamamoto N, Akamatsu N, Sakuraba H, Yamazaki H, Tanoue K. Platelet glycoprotein IV (CD36) deficiency is associated with the absence (type I) or the presence (type II) of glycoprotein IV on monocytes. Blood. 1994;83:392–7. [PubMed]
  • Yanai H, Chiba H, Morimoto M, Jamieson GA, Matsuno K. Type I CD36 deficiency in humans is not associated with insulin resistance syndrome. Thromb Haemost. 2000;83:786. [PubMed]
  • Yesner LM, Huh HY, Pearce SF, Silverstein RL. Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators. Arterioscler Thromb Vasc Biol. 1996;16:1019–25. [PubMed]
  • Yu S, et al. Human peroxisome proliferator-activated receptor alpha (PPARalpha) supports the induction of peroxisome proliferation in PPARalpha-deficient mouse liver. J Biol Chem. 2001;276:42485–91. [PubMed]
  • Zhang X, et al. CD36/fatty acid translocase in rats: distribution, isolation from hepatocytes, and comparison with the scavenger receptor SR-B1. Lab Invest. 2003;83:317–32. [PubMed]
  • Zhao GF, Seng JJ, Zhang H, She MP. Effects of oxidized low density lipoprotein on the growth of human artery smooth muscle cells. Chin Med J (Engl) 2005;118:1973–8. [PubMed]
  • Zhao M, Liu Y, Wang X, New L, Han J, Brunk UT. Activation of the p38 MAP kinase pathway is required for foam cell formation from macrophages exposed to oxidized LDL. Apmis. 2002;110:458–68. [PubMed]
  • Zhou J, et al. A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway. J Biol Chem. 2006;281:15013–20. [PMC free article] [PubMed]
  • Zuckerman SH, Panousis C, Mizrahi J, Evans G. The effect of gamma-interferon to inhibit macrophage-high density lipoprotein interactions is reversed by 15-deoxydelta12,14-prostaglandin J2. Lipids. 2000;35:1239–47. [PubMed]
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