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

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Title Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP
 
Creator Walker, Amy K.
Yang, Fajun
Jiang, Karen
Ji, Jun-Yuan
Watts, Jennifer L.
Purushotham, Aparna
Boss, Olivier
Hirsch, Michael L.
Ribich, Scott
Smith, Jesse J.
Israelian, Kristine
Westphal, Christoph H.
Rodgers, Joseph T.
Shioda, Toshi
Elson, Sarah L.
Mulligan, Peter
Najafi-Shoushtari, Hani
Black, Josh C.
Thakur, Jitendra K.
Kadyk, Lisa C.
Whetstine, Johnathan R.
Mostoslavsky, Raul
Puigserver, Pere
Li, Xiaoling
Dyson, Nicholas J.
Hart, Anne C.
Naar, Anders M.
 
Subject Cholesterol
fasting
lipid
SIRT1
SREBP
 
Description 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.
We thank Kent Golic and the Bloomington Drosophila Stock
Center for dSir2-null flies, and some nematode strains used in
this study were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR)
 
Date 2014-02-24T11:15:32Z
2014-02-24T11:15:32Z
2010
7 May 2010
 
Type Article
 
Identifier Genes Dev. 24(13): 1403-1417
http://hdl.handle.net/123456789/164
 
Language en
 
Publisher Cold Spring Harbor Laboratory Press