Genomic heterogeneity of type II CD36 deficiency

BACKGROUND: CD36 deficiency has been classified in two types, i.e., type I and type II CD36 deficiency. Possible pathological involvement of CD36 deficiency has been suggested in humans, but is still confounding. Homozygous or compound heterozygous mutations (CD36(-/-)) were demonstrated in type I CD36 deficiency, while the genomic or molecular background of type II CD36 deficiency is still unclear, which may bring confounding interpretations of the cause-and-effect events in human CD36 deficiency. In this study, we analyzed the genotype and frequency of type II CD36 deficiency in Japanese populations, and its hereditary pattern in three families. METHODS: Genotypes and protein expression levels of CD36 were examined in 238 Japanese subjects. Genotype was analyzed in the coding region of the CD36 gene. The expression level of CD36 protein was analyzed by flow cytometry after staining with monoclonal anti-CD36 antibody and assessed as mean fluorescence intensity (MFI). RESULTS: Among 238 subjects, subjects for wild-type gene (WT), a single mutation (CD36(+/-)), and CD36(-/-) were 141, 44 and 53, respectively. Monocyte MFI (mean+/-SD) in subjects for WT, CD36(+/-), and CD36(-/-) were 35.7+/-8.5, 15.2+/-3.4, and 0.4+/-0.3, respectively (P<0.0001, between groups). Those of platelets in subjects for WT, CD36(+/-), and CD36(-/-) were 27.1+/-10.6, 11.5+/-6.3, and 0.5+/-0.3, respectively (P<0.0001, between groups). Subjects of both WT and CD36(+/-) were observed in type II CD36 deficiency. Monocyte and platelet MFI in family members of type II CD36 deficiency and 218 unrelated Japanese suggested that the expression level of CD36 protein in monocytes was directly dependent on genotypes. On the other hand, those in platelets were affected by additional heritable factor(s) in addition to the coding region genotype. CONCLUSIONS: MFI in monocytes showed a strong gene-dosage-dependency. On the other hand, MFI in platelets was affected by heritable factor(s) in addition to the coding region genotype, which resulted in heterogeneity of type II CD36 deficiency.     

CD36 may determine our desire for dietary fats

There is a strong link between high fat intake and obesity. In addition to its high caloric density, dietary fat has a hyperphagic effect, in part as a result of its high palatability. The recent identification by Laugerette et al. of CD36 as a taste receptor for fatty acids provides insight into the molecular basis of our preference for fat (see the related article beginning on page 3177). As we gain more information regarding the function of this receptor, we may be able to devise better strategies to address the addictive potential of dietary fat.     

CD36 mediates the innate host response to beta-amyloid

Accumulation of inflammatory microglia in Alzheimer's senile plaques is a hallmark of the innate response to beta-amyloid fibrils and can initiate and propagate neurodegeneration characteristic of Alzheimer's disease (AD). The molecular mechanism whereby fibrillar beta-amyloid activates the inflammatory response has not been elucidated. CD36, a class B scavenger receptor, is expressed on microglia in normal and AD brains and binds to beta-amyloid fibrils in vitro. We report here that microglia and macrophages, isolated from CD36 null mice, had marked reductions in fibrillar beta-amyloid-induced secretion of cytokines, chemokines, and reactive oxygen species. Intraperitoneal and stereotaxic intracerebral injection of fibrillar beta-amyloid in CD36 null mice induced significantly less macrophage and microglial recruitment into the peritoneum and brain, respectively, than in wild-type mice. Our data reveal that CD36, a major pattern recognition receptor, mediates microglial and macrophage response to beta-amyloid, and imply that CD36 plays a key role in the proinflammatory events associated with AD.     

Molecular basis of CD36 deficiency. Evidence that a 478C-->T substitution (proline90-->serine) in CD36 cDNA accounts for CD36 deficiency.

CD36 deficiency is divided into two subgroups: neither platelets nor monocytes express CD36 (type I deficiency), and monocytes express CD36 in spite of the lack of platelet CD36 (type II deficiency). We have already demonstrated that a 478C-->T substitution (proline90-->serine) in platelet CD36 cDNA predominates in type II deficiency (Kashiwagi, H., S. Honda, Y. Tomiyama, H. Mizutani, H. Take, Y. Honda, S. Kosugi, Y. Kanayama, Y. Kurata, and Y. Matsuzawa. 1993. Thromb. Haemostasis. 69:481-484). In this study, we revealed that monocyte CD36 cDNA from two type II deficient subjects was heterozygous for C478 and T478 form, while platelet CD36 cDNA of these subjects consisted of only T478 form. In a type I deficient subject, both platelet and monocyte CD36 cDNA showed only T478 form. Expression assay using C478 or T478 form of CD36 cDNA transfected cells revealed that there was an 81-kD precursor form of CD36, and that the maturation of the 81-kD precursor form to the 88-kD mature form of CD36 was markedly impaired by the substitution. The mutated precursor form of CD36 was subsequently degraded in the cytoplasm. These results indicate that the 478C-->T substitution directly leads to CD36 deficiency via defects in posttranslational modification, and that this substitution is the major defects underlying CD36 deficiency.     

Insulin sensitivity and lipid metabolism in human CD36 deficiency

OBJECTIVE: CD36 has been proposed as a fatty acid translocase and a receptor for HDL and oxidized LDL. The association between CD36 deficiency and insulin resistance remains controversial. We investigated glucose and lipid metabolism in human CD36 deficiency. RESEARCH DESIGN AND METHODS: A total of 61 type I CD36-deficient patients and 25 control subjects were examined. Diabetes was defined as fasting glucose level > or =7 mmol/l or use of hypoglycemic agents. A homeostasis model assessment (HOMA) index was evaluated in patients without diabetes. Insulin resistance was defined as a HOMA index > or =1.73 (sensitivity 64.3%, specificity 78.9%; J Japan Diab Soc, 2000). RESULTS: Diabetes was identified in 12 (20%) of the 61 CD36-deficient patients. Fasting glucose, HbA(1c), and total cholesterol levels in the diabetic CD36-deficient patients were significantly higher than in the control subjects and the nondiabetic CD36-deficient patients. Regardless of diabetes, HDL cholesterol concentrations in the CD36-deficient patients were significantly higher than in the control subjects. The nondiabetic CD36-deficient patients had higher triglyceride concentrations than the control subjects, and triglyceride concentrations were higher in the diabetic CD36-deficient patients than in the nondiabetic CD36-deficient patients. The prevalence of insulin resistance in the nondiabetic CD36-deficient patients was similar to that in the control subjects. CONCLUSIONS: Human CD36 deficiency is not necessarily responsible for insulin resistance. Lipid abnormalities in CD36 deficiency may partly depend on the presence of diabetes, and increased levels of triglyceride and HDL cholesterol may be due to impaired binding of fatty acids and HDL to CD36 and subsequent clearance.     

Posttransfusion purpura-like syndrome associated with CD36 (Naka) isoimmunization

BACKGROUND: CD36 deficiency, which could lead to CD36 isoimmunization, has been reported in the Japanese population. CD36 isoantibody has been involved in platelet transfusion refractoriness. CASE REPORT: A 50-year- old woman originally from Corsica developed severe acute thrombocytopenia after massive transfusion. She was found to be CD36 deficient, and platelet immunoassays revealed a CD36 (Naka) platelet isoantibody. Although the involvement of another mechanism could not be entirely ruled out, the thrombocytopenia was attributed to posttransfusion purpura-like syndrome. The antibody was also involved in platelet transfusion refractoriness. CD36 deficiency was present in two members of the patient's family as well. Flow cytometry studies demonstrated the absence of CD36 expression on the surface of blood monocytes and cultured erythroblasts and megakaryocytes from one of the two CD36-deficient family members studied, but, in the absence of previous immunization, these CD36-deficient patients were not isoimmunized. In contrast, CD36 deficiency was not found in a population of 808 healthy blood donors in the Paris, France, area. CONCLUSION: CD36 isoantibody might be involved in some cases of posttransfusion purpura and platelet transfusion refractoriness. These findings also confirm the extremely low frequency of CD36 deficiency among whites.     

Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes

Lymphangiogenesis plays an important role in tumor metastasis and transplant outcome. Here, we show that thrombospondin-1 (TSP-1), a multifunctional extracellular matrix protein and naturally occurring inhibitor of angiogenesis inhibits lymphangiogenesis in mice. Compared with wild-type mice, 6-mo-old TSP-1-deficient mice develop increased spontaneous corneal lymphangiogenesis. Similarly, in a model of inflammation-induced corneal neovascularization, young TSP-1-deficient mice develop exacerbated lymphangiogenesis, which can be reversed by topical application of recombinant human TSP-1. Such increased corneal lymphangiogenesis is also detected in mice lacking CD36, a receptor for TSP-1. In these mice, repopulation of corneal macrophages with predominantly WT mice via bone marrow reconstitution ameliorates their prolymphangiogenic phenotype. In vitro, exposure of WT macrophages to TSP-1 suppresses expression of lymphangiogenic factors vascular endothelial growth factor (VEGF)-C and VEGF-D, but not of a primarily hemangiogenic factor VEGF-A. Inhibition of VEGF-C is not detected in the absence or blockade of CD36. These findings suggest that TSP-1, by ligating CD36 on monocytic cells, acts as an endogenous inhibitor of lymphangiogenesis.     

合肥地区无偿献血人群CD36抗原缺失的调查

目的 研究合肥地区无偿献血人群CD36抗原的缺失频率.方法 随机留取合肥市中心血站2020年3月～2020年7月血小板无偿捐献者血样973例,流式细胞术检测CD36抗原.EDTA抗凝全血离心制备富血小板血浆,进行血小板CD36抗原检测,下层细胞经红细胞裂解液处理后,进行单核细胞CD36抗原检测.结果 973例血小板无偿...     

CD36 modulation in the subintimal trapping and LDL-mediated migration of macrophages

Evaluation of: Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. J. Clin. Invest. 119, 136–145 (2009).

Atherosclerosis is an immune-mediated chronic inflammatory disease and the leading cause of death in developed countries. It is characterized by the subintimal deposition of oxidized LDL, which triggers a cascade of inflammatory reactions resulting in the formation of atheromatous plaques, narrowing the arterial lumen and, on rupture, leading to thrombotic complications. Macrophages are a central part of this process, their primary role being the phagocytosis of the LDL particles. However, once this has been accomplished, the macrophages can remain resident in the atheroma, rather than leaving it. This leads to progression of the atherosclerotic plaques. The paper discussed has identified a possible mechanism responsible for trapping macrophages within the intima. This may have significant clinical implications since, by blocking this process, reversal of the atherosclerotic process may be possible.     

Parkin reinvents itself to regulate fatty acid metabolism by tagging CD36

Parkinson disease (PD) is a relatively common neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. About 5%-10% of PD cases are inherited. Mutations in the Parkin gene, which encodes a protein that can function as an E3 ubiquitin ligase, are a common cause of familial PD. Such mutations act in a loss-of-function manner and impair the ability of the encoded protein to mediate substrate ubiquitination, although the subsequent molecular pathway that precipitates neuronal degeneration is poorly defined. In this issue of the JCI, Kim and colleagues describe painstaking evidence using a number of dissecting approaches in intact animals and cultured cells to functionally link Parkin and the class B scavenger receptor CD36, suggesting a novel and complex connection between PD and fatty acid metabolism.     

CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis

Phagocyte recognition and ingestion of intact cells undergoing apoptosis are key events in this generally important program of cell death. Insufficient phagocyte capacity for apoptotic cells can result in failure to clear dying cells before membrane integrity is lost, resulting in leakage of noxious cell contents and severe tissue damage. However, no means has been available to increase phagocytic clearance of apoptotic cells. We now report that transfection of the macrophage adhesion molecule CD36 into human Bowes melanoma cells specifically conferred greatly increased capacity to ingest apoptotic neutrophils, lymphocytes, and fibroblasts, comparable to that exhibited by macrophages. Furthermore, when CD36 was transfected into another cell type with limited capacity to take up apoptotic bodies, the monkey COS- 7 cell, similar effects were observed. Therefore, CD36 gene transfer can confer "professional" capacity to ingest apoptotic cells upon "amateur" phagocytes.     

CD36 deficiency is frequent and can cause platelet immunization in Africans

BACKGROUND: CD36 is expressed on several cell lineages. About 5 to 10 percent of Asians lack platelet membrane CD36 (pCD36), but the frequency of pCD36 deficiency in other ethnic groups is not known. Persons who are pCD36-negative are apparently healthy but can develop CD36 isoimmunization. STUDY DESIGN AND METHODS: The pCD36 phenotype was studied in 1885 subjects belonging either to a group of 1127 healthy French blood donors (almost all of whom were white Europeans) or to a group of 758 patients of known ethnic origin. RESULTS: No pCD36-negative persons were found among the blood donors. Only 1 of the 301 white European patients was pCD36-negative. In contrast, 16 of the 206 sub-Saharan Africans was pCD36-negative, a proportion higher than that among that black Caribbeans (1/148, p<0.01). The frequency of pCD36-negative patients was similar in blacks with and without sickle cell disease. Monocyte CD36 (mCD36) expression was studied in 15 of 22 pCD36-negative individuals: it was <10 percent in 7 subjects (type I deficiency) and between 12 and 100 percent in 8 others (type II deficiency). Thirteen pCD36-negative individuals had risk factors for immunization, and 4 had anti-CD36. Some had a history resembling posttransfusion purpura (n = 2), platelet transfusion refractoriness (n = 1), and recurrent miscarriage (n = 1). No correlation was found between immunization and the amount of mCD36. Anti-CD36 from an immunized type II-deficient woman reacted with monocytes from normal controls but not with monocytes from type I- or type II-deficient individuals, and thus it is postulated that mCD36 could be structurally different in normal and type II CD36-deficient individuals. CONCLUSION: CD36 deficiency is frequent in sub-Saharan Africans; development of anti-CD36 can lead to serious complications in multiply transfused patients, such as those with sicke cell disease.     

小鼠CD36在oxLDL降低MnSOD活性中的相关性研究

目的探讨CD36在氧化低密度脂蛋白(ox LDL)降低锰超氧化物歧化酶(Mn SOD)活性中的作用。方法将培养的小鼠平滑肌细胞根据CD36表达情况分为A、B、C三个组:A组将CD36表达后抑制MODOS活性的平滑肌细胞加入ox LDL建立细胞钙化模型;B组则仅仅加入ox LDL建立细胞钙化模型;C组加入可以使CD36超表达NR4AI基因后加入ox LDL建立细胞钙化模型。分别测定A、B、C三个组样本中的钙化平滑肌细胞中CD36以及Mn SOD含量,并通过函数图象探讨分析钙化平滑肌细胞中CD36与Mn SOD含量之间可能存在的联系。结果随着CD36表达的增多,MnSOD含量具有下降趋势,经相关性分析发现两者呈负相关。结论 CD36能够降低Mn SOD的活性,而Mn SOD与动脉硬化密切相关,因此小鼠平滑肌细胞动脉硬化的发生可能与CD36抑制了Mn SOD的表达有关。     

Knob-independent cytoadherence of Plasmodium falciparum to the leukocyte differentiation antigen CD36

The survival of Plasmodium falciparum-infected erythrocytes is enhanced by the sequestration of mature trophozoites and schizonts from the peripheral circulation. Cytoadherence of infected erythrocytes in vivo is associated with the presence of knobs on the erythrocyte surface, but we and others have shown recently that cytoadherence to C32 melanoma cells may occur in vitro in the absence of knobs. We show here that a knobless clone of P. falciparum adheres to the leukocyte differentiation antigen, CD36, suggesting that binding to CD36 is independent of the presence of knobs on the surface of the infected erythrocyte. This clone showed little cytoadherence to immobilized thrombospondin or to endothelial cells expressing the intercellular adhesion molecule 1. Furthermore, an Mr approximately 300-kD trypsin-sensitive protein doublet was immunoprecipitated from knobless trophozoite-infected erythrocytes. Finding a P. falciparum erythrocyte membrane protein 1 (PfEMP1)-like molecule on these infected erythrocytes is consistent with a role for PfEMP1 in cytoadherence to CD36 and C32 melanoma cells.