Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP
- Amy K. Walker1,
- Fajun Yang1,2,8,
- Karen Jiang1,
- Jun-Yuan Ji1,9,
- Jennifer L. Watts3,
- Aparna Purushotham4,
- Olivier Boss5,
- Michael L. Hirsch5,
- Scott Ribich5,
- Jesse J. Smith5,
- Kristine Israelian5,
- Christoph H. Westphal5,
- Joseph T. Rodgers2,6,
- Toshi Shioda1,
- Sarah L. Elson7,
- Peter Mulligan1,2,
- Hani Najafi-Shoushtari1,2,
- Josh C. Black1,
- Jitendra K. Thakur1,2,10,
- Lisa C. Kadyk7,
- Johnathan R. Whetstine1,
- Raul Mostoslavsky1,
- Pere Puigserver2,6,
- Xiaoling Li4,
- Nicholas J. Dyson1,
- Anne C. Hart11 and
- Anders M. Näär1,2,12
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA;
- 2Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA;
- 4National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA;
- 5Sirtris, a GSK company, Cambridge, Massachusetts 02139, USA;
- 6Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
- 7Exelixis, Inc., San Francisco, California 94080, 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.
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Footnotes
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↵12 Corresponding author.
E-MAIL naar{at}helix.mgh.harvard.edu; FAX (617) 726-7808.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1901210.
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Supplemental material is available at http://www.genesdev.org.
- Received December 31, 2009.
- Accepted May 7, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press