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.
authors: Department of Medicine, Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02481, USA.
authors: Yu
authors: Y
authors: Li
authors: Department of Medicine, Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02481, USA.
authors: Shanqin
authors: S
authors: Xu
authors: Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Maria M
authors: MM
authors: Mihaylova
authors: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors: Bin
authors: B
authors: Zheng
authors: Department of Medicine, Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02481, USA.
authors: Xiuyun
authors: X
authors: Hou
authors: Department of Medicine, Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02481, USA.
authors: Bingbing
authors: B
authors: Jiang
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Ogyi
authors: O
authors: Park
authors: Department of Medicine, Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02481, USA.
authors: Zhijun
authors: Z
authors: Luo
authors: Lyon University, INSERM U1060, INRA U1235, CarMeN Laboratory, University Lyon-1, F- 69600 Oullins, France.
authors: Etienne
authors: E
authors: Lefai
authors: Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92093, USA.
authors: John Y-J
authors: JY
authors: Shyy
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Bin
authors: B
authors: Gao
authors: Institut de Recherche Servier, 92150 Suresnes, France.
authors: Michel
authors: M
authors: Wierzbicki
authors: Institut de Recherche Servier, 92150 Suresnes, France.
authors: Tony J
authors: TJ
authors: Verbeuren
authors: Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Reuben J
authors: RJ
authors: Shaw
authors: Department of Medicine, Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02481, USA.
authors: Richard A
authors: RA
authors: Cohen
authors: Department of Medicine, Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02481, USA. Electronic address: mwzang1@bu.edu.
authors: Mengwei
authors: M
authors: Zang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D001578:Benzopyrans / Q000627:therapeutic use; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy*; D006801:Humans; D007333:Insulin Resistance; D050155:Lipogenesis; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D010766:Phosphorylation; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C438505:6,8-diallyl 5,7-dihydroxy 2-(2-allyl 3-hydroxy 4-methoxyphenyl)1-H benzo(b)pyran-4-one; D001578:Benzopyrans; D004041:Dietary Fats; D011973:Receptors, LDL; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D008687:Metformin; D055372:AMP-Activated Protein Kinases