Protein kinase Cbeta mediates hepatic induction of sterol-regulatory element binding protein-1c by insulin

Journal of Lipid Research

Akimitsu Takahashi¹  Noriyuki Inoue¹  Kazuhisa Watanabe¹  Yoshimi Nakagawa¹  Naoya Yahagi¹  Takashi Matsuzaka¹  Yoshinori Takeuchi¹  Takashi Yamamoto¹  Kazuto Kobayashi¹  Nobuhiro Yamada¹  Naomi Ishigaki¹  Shigeru Yatoh¹  Hiroaki Suzuki¹  Takanari Gotoda²  Hitoshi Shimano³ 

[1]Department of Internal Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan

[2]Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

[3]To whom correspondence should be addressed

关键词: SREBP;    lipogenesis;    fatty acid;    triglyceride;    glucose;   

DOI  :  

来源: DOAJ

【 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.

【 授权许可】

Unknown