Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.
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.
Walker
Amy K
AK
Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.
Yang
Fajun
F
Jiang
Karen
K
Ji
Jun-Yuan
JY
Watts
Jennifer L
JL
Purushotham
Aparna
A
Boss
Olivier
O
Hirsch
Michael L
ML
Ribich
Scott
S
Smith
Jesse J
JJ
Israelian
Kristine
K
Westphal
Christoph H
CH
Rodgers
Joseph T
JT
Shioda
Toshi
T
Elson
Sarah L
SL
Mulligan
Peter
P
Najafi-Shoushtari
Hani
H
Black
Josh C
JC
Thakur
Jitendra K
JK
Kadyk
Lisa C
LC
Whetstine
Johnathan R
JR
Mostoslavsky
Raul
R
Puigserver
Pere
P
Li
Xiaoling
X
Dyson
Nicholas J
NJ
Hart
Anne C
AC
Näär
Anders M
AM
D000107:Acetylation; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D017173:Caenorhabditis elegans; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D005215:Fasting / Q000502:physiology*; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D051379:Mice; D009284:Naphthols / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D037761:Sirtuins / Q000037:antagonists & inhibitors; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*
D001549:Benzamides; D006576:Heterocyclic Compounds, 4 or More Rings; D008055:Lipids; D009284:Naphthols; C525422:SRT1720; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; C439060:sirtinol; D009536:Niacinamide; D002784:Cholesterol; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins