AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice

Yu Li, Shanqin Xu, Maria M. Mihaylova, Bin Zheng, Xiuyun Hou, Bingbing Jiang, Ogyi Park, Zhijun Luo, Etienne Lefai, John Y.J. Shyy, Bin Gao, Michel Wierzbicki, Tony J. Verbeuren, Reuben J. Shaw, Richard A. Cohen, Mengwei Zang

Research output: Contribution to journalArticle

Abstract

AMPK has emerged as a critical mechanism for salutary effects of polyphenols on lipid metabolic disorders in type 1 and type 2 diabetes. Here we demonstrate that AMPK interacts with and directly phosphorylates sterol regulatory element binding proteins (SREBP-1c and -2). Ser372 phosphorylation of SREBP-1c by AMPK is necessary for inhibition of proteolytic processing and transcriptional activity of SREBP-1c in response to polyphenols and metformin. AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation. Hepatic activation of AMPK by the synthetic polyphenol S17834 protects against hepatic steatosis, hyperlipidemia, and accelerated atherosclerosis in diet-induced insulin-resistant LDL receptor-deficient mice in part through phosphorylation of SREBP-1c Ser372 and suppression of SREBP-1c- and -2-dependent lipogenesis. AMPK-dependent phosphorylation of SREBP may offer therapeutic strategies to combat insulin resistance, dyslipidemia, and atherosclerosis.

Original languageEnglish (US)
Pages (from-to)376-388
Number of pages13
JournalCell Metabolism
Volume13
Issue number4
DOIs
StatePublished - Apr 6 2011

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Li, Y., Xu, S., Mihaylova, M. M., Zheng, B., Hou, X., Jiang, B., Park, O., Luo, Z., Lefai, E., Shyy, J. Y. J., Gao, B., Wierzbicki, M., Verbeuren, T. J., Shaw, R. J., Cohen, R. A., & Zang, M. (2011). AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metabolism, 13(4), 376-388. https://doi.org/10.1016/j.cmet.2011.03.009