Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

  1. Anders M. Näär1,2,12
  1. 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA;
  2. 2Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
  3. 3School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA;
  4. 4National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA;
  5. 5Sirtris, a GSK company, Cambridge, Massachusetts 02139, USA;
  6. 6Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
  7. 7Exelixis, Inc., San Francisco, California 94080, USA
    • 8 Present addresses: Albert Einstein College of Medicine, Bronx, New York 10461, USA;

    • 9 Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA;

    • 10 National Institute for Plant Genome Research, Aruna Asaf Ali Marg, New Delhi 110067, India;

    • 11 Brown University, Providence, Rhode Island 02912, USA.

    Abstract

    The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD+-dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis.

    Keywords

    Footnotes

    • Received December 31, 2009.
    • Accepted May 7, 2010.
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