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The autoloop pathogenic mechanism of diabetic complication by SREBP-1c

SREBP-1c研究糖尿病并发症的autoloop致病机制

基本信息

批准号：
20591043
负责人：
KOBAYASHI Kazuto
金额：
$ 2.91万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

Sterol-regulatory element binding protein-1c (SREBP-1c) is a transcription factor that controls lipogenesis in the liver. Hepatic SREBP-1c is nutritionally regulated, and its sustained activation causes hepatic steatosis and insulin resistance. Although regulation of SREBP-1c is known to occur at the transcriptional level, the precise mechanism by which insulin signaling activates SREBP-1c promoter remains to be elucidated. Here we show that protein kinase C beta (PKCbeta) is a key mediator of insulin-mediated activation of hepatic SREBP-1c and its target lipogenic genes. Activation of SREBP-1c in the liver of refed mice was suppressed by either adenoviral RNAi-mediated knockdown or dietary administration of a specific inhibitor of protein kinase C beta. The effect of PKCbeta inhibition was cancelled in insulin depletion by streptozotocin (STZ) treatment of mice. Promoter analysis indicated that PKCbeta activates SREBP-1c promoter through replacement of Sp3 by Sp1 for binding to the GC box in the sterol regulatory element (SRE) complex, a key cis-element of SREBP-1c promoter. Knockdown of Sp proteins demonstrated that Sp3 and Sp1 play reciprocally negative and positive roles in nutritional regulation of SREBP-1c, respectively. This new understanding of PKCbeta involvement in nutritional regulation of SREBP-1c activation provides a new aspect of PKCbeta inhibition as a potential therapeutic target for diabetic complications.

固醇调节元件结合蛋白-1c（SREBP-1c）是一种控制肝脏脂肪生成的转录因子。肝脏SREBP-1c受营养调节，其持续激活导致肝脏脂肪变性和胰岛素抵抗。尽管已知SREBP-1c的调控发生在转录水平，但胰岛素信号激活SREBP-1c启动子的确切机制仍有待阐明。在这里，我们发现蛋白激酶C β（PKC β）是胰岛素介导的肝SREBP-1c及其靶脂肪生成基因激活的关键介质。通过腺病毒RNAi介导的敲除或饮食给予蛋白激酶C β的特异性抑制剂，抑制了再饲养小鼠肝脏中SREBP-1c的激活。链脲佐菌素（STZ）治疗小鼠胰岛素耗竭时，PKC β抑制作用被取消。启动子分析表明，PKC β通过Sp1取代Sp3与固醇调节元件（sterol regulatory element，SRE）复合物中的GC盒结合而激活SREBP-1c启动子，该元件是SREBP-1c启动子的关键顺式元件。Sp3和Sp1分别在SREBP-1c的营养调控中起负性和正性作用。这种对PKC β参与营养调节SREBP-1c激活的新认识为PKC β抑制作为糖尿病并发症的潜在治疗靶点提供了新的方面。