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

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591043
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: University of Tsukuba
• Principal Investigator: KOBAYASHI Kazuto University of Tsukuba, 大学院・人間総合科学研究科, 講師 (30455935)
• Co-Investigator(Kenkyū-buntansha): NAKAGAWA Yoshimi 筑波大学, 大学院・人間総合科学研究科, 講師 (80361351) ; SUZUKI Hiroaki 筑波大学, 大学院・人間総合科学研究科, 准教授 (40344890)
• Project Period (FY): 2008 – 2010
• Keywords: メタボリックシンドローム / 脂質代謝 / 遺伝子発現

Research Abstract

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.

Research Products

• [Journal Article] Protein kinase Cbeta mediates hepatic induction of sterol regulatory element-binding protein-1c by insulin. (2010)
  • Author(s): Yamamoto T, Watanabe K, Inoue N, Nakagawa Y, Ishigaki N, Matsuzaka T, Takeuchi Y, Kobayashi K, Yatoh S, Takahashi A, Suzuki H, Yahagi N, Gotoda T, Yamada N, Shimano H
  • Journal Title: J Lipid Res. 51(7) Pages: 1859-70
  • Peer Reviewed
• [Remarks] ホームページ等
  • URL: http://www.md.tsukuba.ac.jp/clinical-med/endocrinology/research/