Hyperglycemia suppresses hepatic scavenger receptor class B type I expression.
Hyperglycemia suppresses hepatic scavenger receptor class B type I expression.
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DOI：
10.1152/ajpendo.00023.2007
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发表时间：
2008
期刊：
影响因子：
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通讯作者：
K. Murao;Xiao Yu;H. Imachi;W. Cao;Ke Chen;Kensuke Matsumoto;T. Nishiuchi;N. Wong;T. Ishida
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文献类型：
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作者：
K. Murao;Xiao Yu;H. Imachi;W. Cao;Ke Chen;Kensuke Matsumoto;T. Nishiuchi;N. Wong;T. Ishida
高血糖是动脉粥样硬化性疾病的主要危险因素。肝脏清道夫受体B类I型（SR-BI）结合HDL颗粒，介导逆向胆固醇运输，从而降低动脉粥样硬化的风险。我们在HepG2细胞和全动物中检测了葡萄糖对SR-BI基因表达的调节。结果显示，暴露于22.4 mM和5.6 mM葡萄糖48小时后，肝脏SR-BI mRNA、蛋白质和从HDL摄取的胆固醇减少了一半。与细胞培养模型一样，糖尿病大鼠肝脏中SR-BI的表达低于正常血糖大鼠。人SR-BI启动子的转录活性与内源性基因表达平行，并且这种活性依赖于葡萄糖的剂量。接下来，我们使用选定信号转导途径的抑制剂来证明SR-BI的葡萄糖抑制对p38 MAPK抑制剂敏感。在存在或不存在葡萄糖的情况下，组成活性p38 MAPK的表达抑制SR-BI启动子的活性。显性阴性的p38 MAPK消除了葡萄糖对启动子活性的抑制作用。缺失分析定位了一个50bp的启动子片段，该片段介导了葡萄糖的作用。在这个DNA片段中有几个特异性蛋白-1 （Sp1）结合位点，Sp1的细胞敲除消除了葡萄糖对其的抑制作用。总之，这些结果表明葡萄糖对SR-B1表达的抑制部分是由p38 MAPK-Sp1通路的激活介导的，并提出了高糖条件下肝脏SR-BI表达的抑制可能为糖尿病患者加速动脉粥样硬化提供了一种机制。
Hyperglycemia is a major risk factor for atherosclerotic disease. Hepatic scavenger receptor class B type I (SR-BI) binds HDL particles that mediate reverse cholesterol transport and thus lowers the risk of atherosclerosis. Here we examined glucose regulation of SR-BI gene expression in both HepG2 cells and whole animals. Results showed that hepatic SR-BI mRNA, protein, and uptake of cholesterol from HDL were halved following 48 h of exposure to 22.4 vs. 5.6 mM glucose. As in the case of the cell culture model, hepatic expression of SR-BI was lower in diabetic rats than in euglycemic rats. Transcriptional activity of the human SR-BI promoter paralleled endogenous expression of the gene, and this activity was dependent upon the dose of glucose. Next, we used inhibitors of select signal transduction pathways to demonstrate that glucose suppression of SR-BI was sensitive to the p38 MAPK inhibitor. Expression of a constitutively active p38 MAPK inhibited SR-BI promoter activity in the presence or absence of glucose. A dominant-negative p38 MAPK abolished the inhibitory effect of glucose on promoter activity. Deletional analysis located a 50-bp fragment of the promoter that mediated the effects of glucose. Within this DNA fragment there were several specificity protein-1 (Sp1) binding sites, and cellular knockdown of Sp1 abrogated its suppression by glucose. Together, these results indicate that the glucose suppression of SR-B1 expression is partially mediated by the activation of the p38 MAPK-Sp1 pathway and raise the possibility that the inhibition of hepatic SR-BI expression under high-glucose conditions provides a mechanism for accelerated atherosclerosis in diabetics.