title: 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.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Walker
authors.forename: Fajun
authors.initials: F
authors.lastname: Yang
authors.forename: Karen
authors.initials: K
authors.lastname: Jiang
authors.forename: Jun-Yuan
authors.initials: JY
authors.lastname: Ji
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Watts
authors.forename: Aparna
authors.initials: A
authors.lastname: Purushotham
authors.forename: Olivier
authors.initials: O
authors.lastname: Boss
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hirsch
authors.forename: Scott
authors.initials: S
authors.lastname: Ribich
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.forename: Kristine
authors.initials: K
authors.lastname: Israelian
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Westphal
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Rodgers
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Elson
authors.forename: Peter
authors.initials: P
authors.lastname: Mulligan
authors.forename: Hani
authors.initials: H
authors.lastname: Najafi-Shoushtari
authors.forename: Josh C
authors.initials: JC
authors.lastname: Black
authors.forename: Jitendra K
authors.initials: JK
authors.lastname: Thakur
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Kadyk
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dyson
authors.forename: Anne C
authors.initials: AC
authors.lastname: Hart
authors.forename: Anders M
authors.initials: AM
authors.lastname: Näär
mesh_terms: 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*
chemical_list: 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