Roles of CD36 and SR-BI as novel AGE-receptors

CD36 和 SR-BI 作为新型 AGE 受体的作用

• 批准号: 13470228
• 负责人: HORIUCHI Seikoh
• 金额: $ 9.28万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470228/
• 关键词: Diabetic Complications; Maillard Reaction Endproducts; AGE; AGE-Receptor; CD36; SR-BI; Atherosclerosis; Reverse Cholesterol Transport

In the Maillard reaction, the reaction of proteins with glucose or other reduced sugars leads, through the Schiff base and Amadori product, to the formation of advanced glycation endproducts (AGE). Recent studies of AGE-structures in vivo as well as the AGE-receptors have emphasized the involvement of post-translational AGE-modification in aging and age-enhanced disease processes such as diabetic complications and atherosclerosis. Three AGE-receptors such as SR-A (type A scavenger receptor), galectin-3 and RAGE (receptor tor AGE) were known. Our recent studies identified CD36 and SR-BI as novel AGE-receptors; CD36-overexpressed CHO cells showed endocytic uptake and subsequent intracellular degradation of AGE-proteins, suggesting that AGE-proteins ate recognized by CD36, which might contribute to the pathogenesis of diabetic vascular complications. By using SR-BI-overexpressed CHO cells (SR-BI-CHO), we showed that SR-BI-mediated selective uptake of cholesteryl esters of HDL as well as H … More DL-mediated cholesterol efflux from SR-BI-CHO cells were effectively inhibited by AGE-proteins, indicating that AGE-proteins play a significant role in HDL-mediated reverse cholesterolIn the present study, we examined effects of AGE-ligands on the function of CD36 and SR-BI. The following results were obtained (i) In addition to glucose-modified AGE-proteins, proteins modified by glyeolaldehyde and methylglyoxal, intermediate aldehydes mediating the AGE-formation in vivo, could induce not only the expression of CD36 in human monocyte macrophages at mRNA and protein levels, but also accelerate ox-LDL-induced foam cell formation. These phenomena were effectively inhibited (neutralized) by anti-CD36 antibody, (ii) These AGB-proteins generated by glycolaldehyde and methylglyoxal could inhibit the selective CE-uptake by mouse primary hepatocytes from HDL.These results have clarified that AGE-ligands generated in vivo might enhance the atherogenic process both by accelerating CD36-mediated atherogenic functions and by inhibiting SR-BI-mediated anti-atherogenic functions. Less

在美拉德反应中，蛋白质通过席夫碱和Amadori产物与葡萄糖或其他还原糖反应，形成晚期糖基化终末产物(AGE)。最近对体内AGE结构和AGE受体的研究强调翻译后AGE修饰参与衰老和AGE增强型疾病过程，如糖尿病并发症和动脉粥样硬化。已知的A型清道夫受体SR-A、Galectin-3和RAGE是A型清道夫受体。我们最近的研究确定CD36和SR-BI是新的AGE受体；CD36过表达的CHO细胞显示细胞内摄取AGE蛋白，随后细胞内AGE蛋白降解，提示CD36识别AGE蛋白，这可能参与糖尿病血管并发症的发病机制。通过SR-BI过表达的CHO细胞(SR-BI-CHO)，我们证明了SR-BI介导的胆固醇酯选择性摄取高密度脂蛋白和H-…AGE蛋白能有效地抑制SR-BI-CHO细胞中更多的DL介导的胆固醇外流，表明AGE蛋白在高密度脂蛋白介导的胆固醇逆转中起着重要作用。结果表明：(1)除葡萄糖修饰的AGE蛋白外，体内介导AGE形成的中间醛乙二醛和甲乙醛修饰的AGE蛋白不仅能在mRNA和蛋白水平上诱导人单核巨噬细胞CD36的表达，而且还能促进ox-LDL诱导的泡沫细胞的形成。这些现象可以被抗CD36抗体有效地抑制(中和)，(Ii)这些由乙醇醛和甲乙醛产生的AGB蛋白可以抑制小鼠肝细胞选择性地从HDL摄取CE。这些结果表明，体内产生的AGE配体可能通过促进CD36介导的动脉粥样硬化形成功能和通过抑制SR-BI介导的抗动脉粥样硬化功能来增强动脉粥样硬化的形成过程。较少

项目成果

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Kato S.等人：“晚期糖基化终产物修饰的超氧化物歧化酶-1 (SOD1) 的形成是导致 SOD1 基因突变的家族性肌萎缩侧索硬化症患者常见包涵体的机制之一，而转基因

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Nagai R., et al.: "Identification in human atherosclerotic lesions of GA-pyridine, a novel structure derived from glycolaldehyde-modified proteins"J.Biol.Chem.. 277. 48905-48912 (2002)

Nagai R.等人：“GA-吡啶在人类动脉粥样硬化病变中的鉴定，这是一种源自乙醇醛修饰蛋白的新型结构”J.Biol.Chem.. 277. 48905-48912 (2002)

Shibata N., Nagai R., Uchida K., Horiuchi S., Yamada S., Hirano A., Kawaguchi M., Yamamoto T., Sasaki S., Kobayashi M.: "Morphological evidence for lipid peroxidalion and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis pa

Shibata N.、Nagai R.、Uchida K.、Horiuchi S.、Yamada S.、Hirano A.、Kawaguchi M.、Yamamoto T.、Sasaki S.、Kobayashi M.：“脂质过氧化和蛋白质糖氧化的形态学证据