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PubMed1997

CD36 forms covalently associated dimers and multimers in platelets and transfected COS-7 cells.

CD36 is a transmembrane glycoprotein expressed on the surface of a number of cell types. The analysis of CD36 from platelets using immunoblotting, gel filtration, and native PAGE indicated the presence of high molecular complexes exceeding the Mr of monomeric CD36. Experiments using transfected COS-7 cells revealed these complexes were homodimers and -multimers of CD36. The multimers could be dissociated by treatment with a reducing agent, indicating they were formed by intermolecular cysteine-bridging. Mutagenesis of the cDNA for CD36 implicated the cysteines in the extracellular domain of the molecule. The potential physiological roles of CD36 multimerisation are discussed.

Animals↗

PubMed1994

Ultrastructural localization of CD36 in human hepatic sinusoidal lining cells, hepatocytes, human hepatoma (HepG2-A16) cells, and C32 amelanotic melanoma cells.

Ultrastructural localization of CD36 in human hepatic sinusoidal lining cells, hepatocytes, human hepatoma (HepG2-A16) cells, and C32 amelanotic melanoma cells. Experimental Parasitology 79, 383-390. CD36 is expressed in the endothelial cells of some human organs, but the ultrastructural localization of this molecule in the sinusoidal lining cells of human liver is not well established. We report the ultrastructural localization of CD36 in the liver using a novel murine monoclonal antibody against CD36, namely MO30, as a primary antibody. Immunocytochemistry by the postembedding method showed that CD36 was localized in endothelial cells of sinusoids and in hepatocyte microvilli protruding into the space of Disse. Moreover, in cultured human hepatoma (HepG2-A16) cells and C32 amelanotic melanoma cells, MO30 reacted with microvilli. Hence, CD36 expressed on these cells may be involved in recognition and/or entry of these cells by malaria sporozoites.

Amino Acid Sequence↗

PubMed1993

A one-step procedure for purification of bovine mammary epithelial cell CD36.

A simple one-step protocol for the purification of the integral membrane protein CD36 from milk-fat-globule membranes of bovine mammary epithelial cells is described. Nonionic detergent extracts of membrane were chromatographed on hydroxylapatite and pure CD36 was eluted with 1 M NaCl. Other proteins of the milk-fat-globule membrane were eluted after CD36 with phosphate buffer. Human platelet CD36 bound to hydroxylapatite only after neuraminidase treatment. CD36 is an extremely hydrophobic and highly glycosylated protein and previous purification procedures have required multiple steps. Chromatography of CD36 on hydroxylapatite provides a simple and quick method of purification which does not sacrifice yield.

Animals↗

PubMed2001

A patient with type I CD36 deficiency whose myocardium accumulated 123I-BMIPP after 4 years.

A 73-year-old man with aortic regurgitation was examined by 123I-alpha-methyl-p-iodophenylpentadecanoic acid (BMIPP) myocardial single photon emission computed tomography (SPECT) in 1995. Myocardial accumulation was not evident on either the early or the delayed image obtained 15 minutes and 3 hours, respectively, after injecting 123I-BMIPP. Flow cytometric analysis of CD36 expression in monocytes and platelets identified a type I CD36 deficiency. The patient was hospitalized for severe heart failure in 1999. Upon admission, the cardiothoracic ratio on chest X-rays was 73%, and the left ventricular end-diastolic diameter on echocardiograms was enlarged to 77 mm. On the second day, we performed 123I-BMIPP myocardial SPECT. Myocardial accumulation was evident in the delayed, but not in the early image. We repeated 123I-BMIPP myocardial SPECT on the 10th day after admission. Myocardial accumulation was evident on both early and delayed images. 99mTc-tetrofosmin myocardial SPECT was immediately performed after 123I-BMIPP myocardial SPECT to distinguish myocardial from pooling images in the left ventricle, but, because the images from both 99Tc-tetrofosmin and 123I-BMIPP myocardial SPECT were idential, we considered that the 123I-BMIPP myocardial SPECT images reflected the actual myocardial condition. The CD36 molecule transports long-chain fatty acid (LCFA) on the myocardial membrane, but 123I-BMIPP scintigraphy does not show any myocardial accumulation in patients with type I CD36 deficiency, indicating that myocardial LCFA uptake occurs through CD36 on the human myocardial membrane. Even though our patient had type I CD36 deficiency, BMIPP was uptaken by the myocardium during heart failure, suggesting a variant pathway on the human myocardial membrane for LCFA uptake.

Aged↗

PubMed1996

Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog.

Transport of long-chain fatty acids into rat adipocytes was previously shown to be inhibited by the reactive derivative sulfosuccinimidyl oleate consequent to its binding to a membrane protein FAT, which is homologous to CD36. In this report, the ability of the purified protein to bind native fatty acids was investigated. CD36 was isolated from rat adipocytes by phase partitioning into Triton X-114 followed by chromatography on DEAE and then on wheat germ agglutinin. Fatty acid binding was determined by incubating CD36, solubilized in buffer containing 0.1 Triton X-100, with fatty acids at 37 degrees C, and then by adsorbing the unbound ligand with Lipidex 1,000 at 0 degrees C. Bovine serum albumin was used as a positive control and gelatin, a protein that does not bind fatty acids, as a negative control. Measurements with albumin yielded reproducible binding values which were not altered by the presence of 0.1% Triton X-100. Under the same conditions, gelatin yielded reproducibly negative measurements that did not differ significantly from zero. CD36 bound various long-chain fatty acids at low ligand to protein ratios. Warming the protein-FA-Lipidex mixture to 37 degrees C removed the FA off the protein. Thus, binding was reversible and distinct from the palmitoylation of the protein known to occur on an extracellular domain. Comparison of the predicted secondary sequence of CD36 with that of human muscle fatty acid binding protein suggested that a potential binding site for the fatty acid on CD36 may exist in its extracellular segment between residues 127 and 279.

Adipocytes↗

PubMed2005

Vitamin E inhibits CD36 scavenger receptor expression in hypercholesterolemic rabbits.

A numerous studies suggest that Vitamin E has a preventive role in atherosclerosis, although the mechanism of action still remains unclear. CD36, a member of the scavenger receptor family is centrally involved in the uptake of oxidized low density proteins (oxLDLs) from bloodstream. During the atherosclerotic process, the lipid cargo of oxLDL accumulates in macrophages and smooth muscle cells, inducing their pathological conversion to foam cells. In the present study, we investigate the role of Vitamin E on CD36 expression in an in vivo model. Atherosclerosis was induced by a 2% cholesterol containing Vitamin E poor diet. Three groups of six rabbits each were studied. The first group (control) was fed on Vitamin E poor diet. The second group was fed with Vitamin E poor diet containing 2% cholesterol and the rabbits in the third group were fed with Vitamin E poor diet containing 2% cholesterol and received injections of 50 mg/kg of Vitamin E i.m. After 4 weeks, aortas were removed and analysed by light microscopy for atherosclerotic lesions. Aortic samples were analysed for CD36 mRNA expression. The aortas of cholesterol-fed rabbits showed typical atherosclerotic lesions, detected by macroscopic and microscopic examination, and exhibited an increase in CD36 mRNA expression. Vitamin E fully prevented cholesterol induced atherosclerotic lesions and the induction of CD36 mRNA expression. The effects observed at the level of CD36 scavenger receptor expression in vivo suggest an involvement of reduced foam cell formation in the protective effect of Vitamin E against atherosclerosis.

Animals↗

PubMed2004

Estradiol down-regulates CD36 expression in human breast cancer cells.

CD36 is a trans-membrane receptor that regulates apoptosis and angiogenesis in response to its ligand thrombospondin-1 (TSP-1). This study measures expression of CD36 and TSP-1 in breast cancer cell lines. Expression of TSP-1 was approximately 50-fold higher in the aggressive cell line MDA-MB-231 than in less aggressive MCF-7, BT-474, ZR-75 and T47-D cells. In contrast, MDA-MB-231 express 30 to 100-fold less CD36 than less aggressive cells. Hormone-dependent T47-D and MCF-7 cells down-regulate CD36 in response to estradiol, and anti-hormone ICI 182,780 block this effect. These results suggest that the estrogen receptors play a role in regulating CD36 expression and ICI 182,780 prevents loss of CD36 as a novel mechanism for its anti-estrogen effect in breast cancer cells.

Antineoplastic Agents, Hormonal↗

PubMed2006

A CD36-dependent signaling cascade is necessary for macrophage foam cell formation.

Accumulation of macrophage foam cells in atherosclerotic blood vessel intima is a critical component of atherogenesis mediated by scavenger receptor-dependent internalization of oxidized LDL. We demonstrated by coimmunoprecipitation and pull-down assays that the macrophage scavenger receptor CD36 associates with a signaling complex containing Lyn and MEKK2. The MAP kinases JNK1 and JNK2 were specifically phosphorylated in macrophages exposed to oxLDL. Using cells isolated from SRA, TLR2, or CD36 null mice, and phospholipid ligands specific for either SRA or CD36, we showed that JNK activation was mediated by CD36. Both foam cell formation and activation of JNK2 in hyperlipidemic mice were diminished in the absence of CD36. Furthermore, inhibition of Src or JNK blocked oxLDL uptake and inhibited foam cell formation in vitro and in vivo. These findings show that a specific CD36-dependent signaling pathway initiated by oxLDL is necessary for foam cell formation and identify potential targets for antiatherosclerosis therapy.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Adverse prognostic impact of CD36 and CD2 expression in adult de novo acute myeloid leukemia patients.

BACKGROUND AND OBJECTIVES: A consecutive series of acute myeloid leukemias (AML) patients was analyzed in conditions which reduce the inter-assay variations (the same flow cytometer, the same observers and the same panel of monoclonal antibodies) in order to investigate the prognostic information provided by flow cytometry. DESIGN AND METHODS: Two hundred and sixty-six bone marrow (BM) samples from 326 patients enrolled in the LMA-99 protocol from the CETLAM group were studied by multiparametric flow cytometry. Immunophenotyping studies were performed on erythrocyte-lysed BM samples. Antigen expression of leukemic cells was analyzed using triple stainings with fluorochrome-conjugated combinations of monoclonal antibodies. RESULTS: CD2 was positive in 21 cases (8%); an associated inv(16) was detected in eight CD2+ cases (38%). Two-year overall survival (OS) rate for CD2+/inv(16)+ patients was 75%, whereas it was 0% for CD2+/inv(16)- patients and 47% for CD2- patients (p=0.0001). CD36 was expressed in 37% of patients (n=98). Two-year leukemia-free survival (LFS) rate was 34% for CD36+ patients and 55% for CD36- patients (p=0.001). In the multivariate analysis, CD2+ (RR=8.4; p=0.0001) and adverse karyotype (RR=10.2; p=0.0001) were associated with a lower CR rate, CD36+ (RR=1.5; p=0.03), CD2+ (RR=2; p=0.04) and adverse karyotype (RR=4; p=0.0001) were associated with a lower OS and CD36+ (RR=2; p=0.002) and adverse karyotype (RR=3.5; p=0.005) predicted a lower LFS. CONCLUSIONS: CD2+ patients had a very poor OS when CD2/inv(16)+ cases were excluded. CD36 and CD2 expression at diagnosis can provide prognostically important information in adult de novo AML.

Acute Disease↗

PubMed2026

CD36 Influences Leukemia Progression in MLL-AF9-Driven AML by Modulating the Leukemia Immune Microenvironment.

CD36, a fatty-acid translocase, is increasingly implicated in acute myeloid leukemia biology and treatment resistance, yet its contribution to leukemogenesis is still unclear. Using the MLL-AF9 model, we transduced hematopoietic stem/progenitor cells (HSPCs) from Cd36-knockout (KO) or wild-type (WT) mice and assessed leukemic potential with in vitro assays, transplants, and transcriptomic, metabolomic, and immune profiling. Both Cd36KO- and Cd36WT-HSPCs underwent efficient MA9-driven transformation, with comparable colony formation and Hox/Meis1 pathway activation, indicating Cd36 is dispensable for leukemic initiation. However, Cd36 deletion markedly attenuated disease progression, reducing leukemic burden and extending survival in irradiated mice (median 22 vs. 15 days, P = 0.001). Effects were strikingly amplified in immunocompetent, non-irradiated recipients (median 63 vs. 22 days, P = 0.002), revealing immune-dependent suppression. Immune profiling showed enhanced CD4⁺ and CD8⁺ T cell infiltration, reduced CD4⁺CD25⁺ regulatory-like cells, and lower Tim-3 expression in Cd36KO-MA9 spleens, consistent with a less exhausted, more effective anti-leukemic T cell response. Despite enhanced T cell infiltration, TCR repertoires remained conserved, indicating functional reprogramming rather than clonal selection. Consistent with a suppressive leukemia immune microenvironment, RNA-seq gene set enrichment analysis identified upregulation of inflammatory (TNFα/NF-κB) and hypoxic pathways in Cd36WT-MA9 cells. Untargeted metabolomics revealed metabolic shifts in Cd36KO cells, involving a reduction in three key metabolites, UDP-GlcNAc, UDP-Galactose/UDP-Glucose, and O-Phospho-L-Serine, that likely support an immune evasion mechanism. These findings demonstrate that while Cd36 is not essential for MLL-AF9-mediated transformation, its cell-intrinsic expression in leukemic cells suppresses anti-leukemic immunity and accelerates progression. This positions CD36 as a promising target to enhance immune surveillance and limit AML aggressiveness.

Acute Myeloid Leukemia (AML)↗

PubMed2001

Association of the Pro90Ser CD36 mutation with elevated free fatty acid concentrations but not with insulin resistance syndrome in Japanese.

BACKGROUND: CD36 deficiency is reportedly an underlying factor about insulin resistance, defective fatty acid metabolism and hypertriglyceridemia in spontaneously hypertensive rat (SHR), and may be involved in the pathogenesis of insulin resistance and hyperlipidemia in humans. METHODS: We examined 831 adults undergoing health screening. The majority (780) was Pro90 homozygous for the CD36 gene product, but 51 displayed a CD36 mutation (2 homozygous and 49 heterozygous for Ser90). This is the major mutation site involved in CD36 deficiency in Japanese. RESULTS: Among parameters related to insulin resistance, there were no differences in body mass index (BMI), HDL cholesterol, total cholesterol, triglycerides, insulin and insulin resistance index (HOMA IR), or blood pressure between 91 normal subjects (45 male and 46 female) randomly selected from the 780 Pro90 homozygotes and the 51 (29 male and 22 females) CD36-deficient subjects (Ser90 homozygote and Pro90Ser heterozygote). Free fatty acid concentrations, however, were higher in Ser90 CD36 subjects than in Pro90 control subjects. CONCLUSIONS: The CD36Pro90Ser mutation is not necessarily related to the insulin resistance syndrome, but is associated with high free fatty acid concentrations in Japanese.

Adult↗

PubMed2001

Characterization of peroxynitrite-oxidized low density lipoprotein binding to human CD36.

Peroxynitrite-mediated oxidation may be an important physiological mechanism for oxidation of low density lipoprotein (LDL), however, the molecular basis for the interaction of peroxynitrite oxidized LDL (OxLDL) with scavenger receptors such as CD36, has not been characterized. In this study, we compared the biochemical characteristics and receptor binding of LDL that was oxidized using: (1) Cu2+, a standard method of oxidizing LDL in vitro; and (2) 3-morpholinosydnonimine (SIN-1), a source of peroxynitrite. Both methods of oxidation caused an increase in electrophoretic migration of LDL, but greater mobility was observed with Cu2+-OxLDL. In addition, greater fragmentation of apolipoprotein B was observed following Cu2+ oxidation than after SIN-1 oxidation. The levels of lipid peroxides and thiobarbituric acid reactive substances were similar after 20 h of oxidation by both methods, although the time-course was distinct. Cu2+ and SIN-1-OxLDL bound specifically to the macrophage scavenger receptor CD36 with high affinity. Binding of the 20 h SIN-1 treated LDL to CD36 was comparable to a 4 h Cu2+ modified LDL. The binding of Cu2+ and SIN-1-OxLDL to CD36 was similar under different biochemical conditions and modifications of the receptor, suggesting that OxLDL particles, generated by either method, bind to the same domain of CD36. The results demonstrate that SIN-1 produced an oxidized LDL particle that binds specifically to CD36 and suggests that peroxynitrite OxLDL may represent a more physiologically relevant model than Cu2+-OxLDL for studying the interactions of OxLDL with cells and lipoprotein receptors in vitro.

Animals↗

PubMed1998

CD36-dependent adhesion and knob expression of the transmission stages of Plasmodium falciparum is stage specific.

Plasmodium falciparum trophozoites sequester from the peripheral circulation by adherence to host endothelium. Gametocytes, also sequester during maturation. Analysis of the adhesion phenotype of stage I to V gametocytes of several isolates/clones was assessed by binding of infected cells to C32 melanoma cells (C32MC) and the purified adhesion proteins, leucocyte differentiation antigen (CD36) and intercellular adhesion molecule-1 (ICAM-1). These cells and proteins, have previously been shown to be receptors for adherence of trophozoites. Early gametocytes (stages I-IIA) were found to bind to C32MC as well as the purified receptor CD36 but not to ICAM-1. Early gametocytes bound to C32MC via CD36 and the parasite ligand involved in this binding was trypsin sensitive. Stage IIB to V gametocytes did not adhere to C32MC, CD36 nor ICAM-1. Electron-dense protruberances known as knobs and histidine rich protein 1 (HRP 1) expression have been associated with trophozite adhesion to CD36. Knobs were present at the surface of early but not late gametocyte infected cells. Stage-specific patterns of HRP 1 expression, consistent with a role for this molecule in CD36 adhesion of early gametocytes, were also observed. The adhesion phenotype of these young gametocytes was indistinguishable from that of the trophozoites by all criteria examined. These data support the hypothesis that other host receptors mediate the binding of late gametocytes.

Animals↗

PubMed2003

Pathophysiology of human genetic CD36 deficiency.

CD36, originally identified as glycoprotein IV on platelets, is an 88-kDa integral membrane protein that has multiple ligands and is expressed in the cardiovascular system (ie, blood vessel walls and the heart). Human genetic CD36 deficiency is relatively frequent in Asian and African populations. Investigation into the pathophysiology of this disorder has shown that CD36 may play an important role as a major scavenger receptor for oxidized low-density lipoproteins and as a crucial transporter for long-chain fatty acids. The CD36 deficiency may be related to the phenotypic expression of the "metabolic syndrome," which is frequently associated with atherosclerotic cardiovascular diseases. It also has been reported that CD36 deficiency might be linked with cardiomyopathy. These data raised the possibility that CD36 deficiency might be an important genetic background for these life-threatening human cardiovascular diseases.

Animals↗

PubMed2001

A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation.

Both the risk and the rate of development of atherosclerosis are increased in diabetics, but the mechanisms involved are unknown. Here we report a glucose-mediated increase in CD36 mRNA translation efficiency that results in increased expression of the macrophage scavenger receptor CD36. Expression of CD36 was increased in endarterectomy lesions from patients with a history of hyperglycemia. Macrophages that were differentiated from human peripheral blood monocytes in the presence of high glucose concentrations showed increased expression of cell-surface CD36 secondary to an increase in translational efficiency of CD36 mRNA. We obtained similar data from primary cells isolated from human vascular lesions, and we found that glucose sensitivity is a function of ribosomal reinitiation following translation of an upstream open reading frame (uORF). Increased translation of macrophage CD36 transcript under high glucose conditions provides a mechanism for accelerated atherosclerosis in diabetics.

5' Untranslated Regions↗

PubMed1995

Identification of an immunodominant functional domain on human CD36 antigen using human-mouse chimaeric proteins and homologue-replacement mutagenesis.

The human CD36 antigen is a multifunctional membrane glycoprotein that acts as a receptor for thrombospondin, malaria-infected erythrocytes and oxidized low-density lipoprotein, as well as being implicated in the recognition of apoptotic neutrophils by macrophages. OKM5 and other anti-CD36 monoclonal antibodies have been shown to inhibit these CD36 adhesive functions, suggesting that the monoclonal-antibody epitopes and the domains that mediate these events are closely related. Analysis of a series of chimaeric exchanges between human and mouse CD36 shows that six anti-CD36 monoclonal antibodies (OKM5, FA6-152, L103, 5F1, SM phi and 10/5) recognize epitopes within the domain comprising amino acids 155-183. A seventh monoclonal antibody (13/10) binds to another domain that spans amino acids 30-76. Homologue-replacement mutagenesis performed within the human 155-183 immunodominant sequence identifies key residues for the binding of three functional monoclonal antibodies (OKM5, FA6-152 and L103). The fact that antibodies directed against the 155-183 domain can inhibit adhesion suggests that this domain is directly involved in CD36-ligand binding.

Amino Acid Sequence↗

PubMed2000

Hyperexpression of ICAM-1 and CD36 in placentas infected with Plasmodium falciparum: a possible role of these molecules in sequestration of infected red blood cells in placentas.

AIMS: During pregnancy, Plasmodium falciparum malaria is frequent and associated with maternofetal complications. This could be the consequence of sequestration by several adhesion molecules of parasite-infected red blood cells in syncytiotrophoblast. To investigate the expression of ICAM-1 and CD36, two of the adhesion molecules for Plasmodium falciparum, an immunohistochemical study was carried out in malaria-infected placentas. METHODS AND RESULTS: Thirty-five infected and 35 noninfected samples were chosen randomly. According to the histological classification of Bulmer, the infected placentas were separated in three groups: active, active chronic and past-chronic infection. CD36 was localized in the cytoplasm of stromal cells of terminal villi of infected or noninfected placentas, but not in syncytiotrophoblast. ICAM-1 was detected in the cytoplasm of stromal and endothelial villous cells in both infected and noninfected placentas and in syncytiotrophoblast of eight infected placentas showing more frequently active than active chronic or past-chronic infection (P < 0.001). The percentage of cells immunostained for CD36 or ICAM-1 was evaluated in the terminal villi. The proportion of villous cells, with ICAM-1 and CD36 immunostaining, was significantly higher in infected vs. noninfected placentas (P < 0.0001) and CD36 was detected more in acute inflammatory vs. past-chronic inflammatory placentas (P < 0.05). CONCLUSIONS: The higher expression of ICAM-1 in infected placentas and its localization in syncytiotrophoblast particularly during acute infection, suggest ICAM-1 can act directly in the sequestration of parasite-infected red blood cells (IRBCs). On the other hand, the expression of CD36 is influenced by the presence of IRBCs without being directly implicated in sequestration of IRBCs. The hyperexpression of these two molecules could explain the high frequency of malaria during pregnancy.

Adult↗

PubMed1998

Assignment of disulfide bridges in bovine CD36.

The multifunctional membrane protein CD36 is expressed on platelets, mature monocytes and macrophages, microvascular endothelial cells and mammary epithelial cells. The exact physiological function of this glycoprotein is unclear. In order to determine the number and pattern of disulfide bridges, CD36 was purified from bovine milk fat globule membranes. The purification procedure involved Triton X-114 extraction, DEAE-Sepharose ion-exchange chromatography and reverse-phase chromatography on a Resource RPC column. The CD36 preparation was used for characterization of the disulfide bridge pattern, which was determined by peptide mapping, amino acid sequence analysis, and matrix-assisted laser-desorption ionization/time of flight mass spectrometry. We have found that there are no free cysteines in CD36 and that the six centrally clustered cysteines are linked by disulfide bonds, Cys242-Cys310, Cys271-Cys332 and Cys312-Cys321, resulting in a 1-3, 2-6 and 4-5 arrangement of the disulfide bridges. These data are in agreement with a model where the protein is oriented so that it has two short intracellular segments (residues 1-6 and 461-471) and two transmembrane domains (residues 7-28 and 439-460), and with four cysteines expected to be acylated placed near the intracellular side of the membrane. The remaining part of CD36 is extracellular, comprising eight glycosylations and three disulfide bridges. In the CD36 family of membrane proteins, it is likely that a similar pattern of disulfide bridges can be found in the sensory neuron membrane protein-1 from the silk moth Antheraea polyphemus and the mammalian scavenger receptor class B type I, whereas lysosome membrane protein II, and epithelial membrane protein from Drosophila melanogaster are both lacking one cysteine in the area of interest.

Amino Acid Sequence↗