Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell Metab. 2011 Apr 6;13(4):376-388. doi: 10.1016/j.cmet.2011.03.009.

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

Author information

1
Department of Medicine, Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02481, USA.
2
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.
3
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
4
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
5
Lyon University, INSERM U1060, INRA U1235, CarMeN Laboratory, University Lyon-1, F- 69600 Oullins, France.
6
Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92093, USA.
7
Institut de Recherche Servier, 92150 Suresnes, France.
8
Department of Medicine, Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02481, USA. Electronic address: mwzang1@bu.edu.

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.

PMID:
21459323
PMCID:
PMC3086578
DOI:
10.1016/j.cmet.2011.03.009
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center