Journal article
Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP
Genes & development, Vol.24(13), pp.1403-1417
07/01/2010
Handle:
https://hdl.handle.net/2376/109586
PMCID: PMC2895199
PMID: 20595232
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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Details
- Title
- Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP
- Creators
- Amy K Walker - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAFajun Yang - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAKaren Jiang - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAJun-Yuan Ji - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAJennifer L Watts - School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USAAparna Purushotham - National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USAOlivier Boss - Sirtris, a GSK company, Cambridge, Massachusetts 02139, USAMichael L Hirsch - Sirtris, a GSK company, Cambridge, Massachusetts 02139, USAScott Ribich - Sirtris, a GSK company, Cambridge, Massachusetts 02139, USAJesse J Smith - Sirtris, a GSK company, Cambridge, Massachusetts 02139, USAKristine Israelian - Sirtris, a GSK company, Cambridge, Massachusetts 02139, USAChristoph H Westphal - Sirtris, a GSK company, Cambridge, Massachusetts 02139, USAJoseph T Rodgers - Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USAToshi Shioda - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USASarah L Elson - Exelixis, Inc., San Francisco, California 94080, USAPeter Mulligan - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAHani Najafi-Shoushtari - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAJosh C Black - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAJitendra K Thakur - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USALisa C Kadyk - Exelixis, Inc., San Francisco, California 94080, USAJohnathan R Whetstine - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USARaul Mostoslavsky - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAPere Puigserver - Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USAXiaoling Li - National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USANicholas J Dyson - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAAnne C Hart - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USAAnders M Näär - Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA
- Publication Details
- Genes & development, Vol.24(13), pp.1403-1417
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- Cold Spring Harbor Laboratory Press
- Identifiers
- 99900547183301842
- Language
- English
- Resource Type
- Journal article