The autoloop pathogenic mechanism of diabetic complication by SREBP-1c
| Project/Area Number |
20591043
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | University of Tsukuba |
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Principal Investigator |
KOBAYASHI Kazuto University of Tsukuba, 大学院・人間総合科学研究科, 講師 (30455935)
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| 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)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | メタボリックシンドローム / 脂質代謝 / 遺伝子発現 / 栄養代謝 / 転写因子 / 生活習慣病 / SREBP / PKC / 糖尿病 / インスリン / 糖尿病性腎症 / シグナル伝達 / 高血糖 |
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| 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.
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Report
(4 results)
Research Products
(14 results)
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[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
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Journal Title
J Lipid Res. 51(7)
Pages: 1859-70
Related Report
Peer Reviewed
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