AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-Induced Insulin-Resistant Mice
2011
Li, Yu | Xu, Shanqin | Mihaylova, Maria M. | Zheng, Bin | Hou, Xiuyun | Jiang, Bingbing | Park, Ogyi | Luo, Zhijun | Lefai, Etienne | Shyy, John Y. -J. | Gao, Bin | Wierzbicki, Michel | Verbeuren, Tony J. | Shaw, Reuben J. | Cohen, Richard A. | Zang, Mengwei | Boston University [Boston] (BU) | Howard Hughes Med Inst ; The Salk Institute for Biological Studies | Salk Institute for Biological Studies ; Plant Molecular and Cellular Biology Laboratory | Columbia University [New York] | National Institute on Alcohol Abuse and Alcoholism | Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN) ; Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon) ; Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM) | University of California [San Diego] (UC San Diego) ; University of California (UC) | SERVIER | National Institutes of Health [RO1 DK076942, PO1 HL068758, RO1 DK080425, DK59637, R01 DK080425]; American Diabetes Association [1-08-JF-47]
International audience
Show more [+] Less [-]English. 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.
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