Protein Kinase Cbeta Mediates Hepatic Induction of Sterol-regulatory Element Binding Protein-1c by Insulin

Overview

Journal J Lipid Res

Publisher Elsevier

Specialty Biochemistry

Date 2010 Feb 25

PMID 20179320

Citations 17

Authors

Takashi Yamamoto

Kazuhisa Watanabe

Noriyuki Inoue

Yoshimi Nakagawa

Naomi Ishigaki

Takashi Matsuzaka

Yoshinori Takeuchi

Kazuto Kobayashi

Shigeru Yatoh

Akimitsu Takahashi

Hiroaki Suzuki

Naoya Yahagi

Takanari Gotoda

Nobuhiro Yamada

Hitoshi Shimano

Affiliations

Soon will be listed here.

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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