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

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.

• Authors: Amy K Walker, Fajun Yang, Karen Jiang, Jun-Yuan Ji, Jennifer L Watts, Aparna Purushotham, Olivier Boss, Michael L Hirsch, Scott Ribich, Jesse J Smith, Kristine Israelian, Christoph H Westphal, Joseph T Rodgers, Toshi Shioda, Sarah L Elson, Peter Mulligan, Hani Najafi-Shoushtari, Josh C Black, Jitendra K Thakur, Lisa C Kadyk, Johnathan R Whetstine, Raul Mostoslavsky, Pere Puigserver, Xiaoling Li, Nicholas J Dyson, Anne C Hart, Anders M Näär
• Journal: Genes & development (Genes Dev) Vol. 24 Issue 13 Pg. 1403-17 (Jul 01 2010) ISSN: 1549-5477 [Electronic] United States
• PMID: 20595232 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Heterocyclic Compounds, 4 or More Rings
• Lipids
• Naphthols
• SRT1720
• Srebf1 protein, mouse
• Srebf2 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Sterol Regulatory Element Binding Protein 2
• sirtinol
• Niacinamide
• Cholesterol
• Sirt1 protein, mouse
• Sirtuin 1
• Sirtuins

Topics

• Acetylation
• Animals
• Benzamides (pharmacology)
• Caenorhabditis elegans
• Cell Line
• Cholesterol (biosynthesis)
• Down-Regulation (drug effects)
• Fasting (physiology)
• HeLa Cells
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Lipids (biosynthesis)
• Mice
• Naphthols (pharmacology)
• Niacinamide (pharmacology)
• Protein Stability (drug effects)
• Sirtuin 1 (metabolism)
• Sirtuins (antagonists & inhibitors)
• Sterol Regulatory Element Binding Protein 1 (metabolism)
• Sterol Regulatory Element Binding Protein 2 (metabolism)