Yamashita Shizuya, Hirano Ken-ichi, Kuwasako Takahiro, Janabi Mohamed, Toyama Yumiko, Ishigami Masato, Sakai Naohiko
Department of Internal Medicine and Molecular Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Mol Cell Biochem. 2007 May;299(1-2):19-22. doi: 10.1007/s11010-005-9031-4.
Oxidized low density lipoprotein (LDL) (Ox-LDL) plays an important role in the pathogenesis of atherosclerosis. Oxidized LDL is taken up by macrophages via scavenger receptors. CD36 is an 88 kDa glycoprotein expressed on platelets, monocyte-macrophages, microvascular endothelial cells, adipose tissue, skeletal muscles and heart. We found patients with CD36 deficiency and identified several mutations in the CD36 gene. We also reported that CD36-deficient macrophages showed a 50% reduction in the binding of Ox-LDL, suggesting that CD36 is one of the major receptors for Ox-LDL. CD36 was expressed on macrophages in the atherosclerotic lesions of human aorta and coronary arteries especially on foamed macrophages. The distribution of CD36 expression was slightly different from that of scavenger receptor class A types I and II. The expression of CD36 on macrophages was up-regulated by Ox-LDL and down-regulated by interferon gamma. Since CD36 is a transporter of long-chain fatty acids (LCFA), CD36-deficient patients showed a defect in the uptake of an LCFA analog, BMIPP, by the heart. Furthermore, the secretion of IL-1beta and TNF-alpha from monocyte-derived macrophages induced by Ox-LDL was markedly reduced and the activation of NF-kappaB was attenuated in CD36-deficient subjects compared with controls, suggesting that CD36-mediated signaling is also impaired in CD36 deficiency. To elucidate the roles of CD36 in vivo, we characterized the clinical profile of CD36-deficient patients. Most of them were accompanied by hyperlipidemia (mainly hypertriglyceridemia), increased remnant lipoproteins and mild elevation of fasting plasma glucose level and blood pressure. Glucose clamp technique revealed mean whole body glucose uptake was reduced in CD36-deficient patients, indicating the presence of insulin resistance. The frequency of CD36 deficiency was higher in patients with coronary heart disease (CHD) than in control subjects. Taken together, CD36 deficiency is accompanied by (1) hyperlipidemia and increased remnant lipoproteins, (2) impaired glucose metabolism based upon insulin resistance, and (3) mild hypertension, and comprises one of the genetic backgrounds of the metabolic syndrome, leading to the development of CHD.
氧化型低密度脂蛋白（Ox-LDL）在动脉粥样硬化的发病机制中起重要作用。氧化型低密度脂蛋白通过清道夫受体被巨噬细胞摄取。CD36是一种88 kDa的糖蛋白，在血小板、单核细胞 - 巨噬细胞、微血管内皮细胞、脂肪组织、骨骼肌和心脏中表达。我们发现了CD36缺陷患者，并在CD36基因中鉴定出多个突变。我们还报道，CD36缺陷的巨噬细胞对氧化型低密度脂蛋白的结合减少了50%，这表明CD36是氧化型低密度脂蛋白的主要受体之一。CD36在人主动脉和冠状动脉粥样硬化病变中的巨噬细胞上表达，尤其是在泡沫巨噬细胞上。CD36表达的分布与清道夫受体A类I型和II型略有不同。巨噬细胞上CD36的表达被氧化型低密度脂蛋白上调，被干扰素γ下调。由于CD36是长链脂肪酸（LCFA）的转运体，CD36缺陷患者心脏对LCFA类似物BMIPP的摄取存在缺陷。此外，与对照组相比，CD36缺陷受试者中由氧化型低密度脂蛋白诱导的单核细胞衍生巨噬细胞分泌的IL-1β和TNF-α明显减少，NF-κB的激活减弱，这表明CD36介导的信号传导在CD36缺陷中也受损。为了阐明CD36在体内的作用，我们对CD36缺陷患者的临床特征进行了描述。他们中的大多数伴有高脂血症（主要是高甘油三酯血症）、残余脂蛋白增加以及空腹血糖水平和血压轻度升高。葡萄糖钳夹技术显示，CD36缺陷患者的平均全身葡萄糖摄取减少，表明存在胰岛素抵抗。冠心病（CHD）患者中CD36缺陷的频率高于对照组。综上所述，CD36缺陷伴有（1）高脂血症和残余脂蛋白增加，（2）基于胰岛素抵抗的糖代谢受损，以及（3）轻度高血压，是代谢综合征的遗传背景之一，导致冠心病的发生。
