@article{704400e218274f4ebc9040f15d40610e,
title = "AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice",
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.",
author = "Yu Li and Shanqin Xu and Mihaylova, {Maria M.} and Bin Zheng and Xiuyun Hou and Bingbing Jiang and Ogyi Park and Zhijun Luo and Etienne Lefai and Shyy, {John Y.J.} and Bin Gao and Michel Wierzbicki and Verbeuren, {Tony J.} and Shaw, {Reuben J.} and Cohen, {Richard A.} and Mengwei Zang",
note = "Funding Information: This work has been supported by the National Institutes of Health Grants RO1 DK076942 (to M.Z.), PO1 HL068758 (to R.A.C.), R01 DK080425 (to R.J.S.), and DK59637 (Lipid, Lipoprotein, and Atherosclerosis Core of the Vanderbilt Mouse Metabolic Phenotype Center), and the American Diabetes Association Junior Faculty Award 1-08-JF-47 (to R.J.S.). M.Z. and R.A.C. are recipients of Robert Dawson Evans Junior Faculty Merit and Scholar Awards. M.Z. is also the recipient of the Wing Tat Lee Award at Boston University School of Medicine. This work was also supported by NIH R01 DK080425 (to R.J.S.). We are grateful to Dr. Benoit Viollet for kindly providing AMPK +/+ and AMPK −/− MEFs. We thank Jianxin Xie at Cell Signaling Technology for collaborating to develop the phospho-Ser372 SREBP-1c antibody. We would like to thank Dr. Vladimir R. Babaev for helping to perform FPLC analysis. We also thank Kimberly Wong and Dr. Yuxia Cao for excellent technical assistance and Karlene A. Maitland-Toolan and Robert M. Weisbrod for animal studies. We would like to thank Dr. Kenneth Walsh, Dr. Sudha B. Biddinger, Dr. Dave Pimental, and Dr. Haya Herscovitz for insightful discussion. Dr. Tony J. Verbeuren and Dr. Michel Wierzbicki are employees and Dr. Richard A. Cohen is a consultant of Servier Pharmaceutical Company. ",
year = "2011",
month = apr,
day = "6",
doi = "10.1016/j.cmet.2011.03.009",
language = "English (US)",
volume = "13",
pages = "376--388",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",
}