title: Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6.
abstract: Cholesterol homeostasis is crucial for cellular function and organismal health. The key regulator for the cholesterol biosynthesis is sterol-regulatory element binding protein (SREBP)-2. The biochemical process and physiological function of SREBP-2 have been well characterized; however, it is not clear how this gene is epigenetically regulated. Here we have identified sirtuin (Sirt)6 as a critical factor for Srebp2 gene regulation. Hepatic deficiency of Sirt6 in mice leads to elevated cholesterol levels. On the mechanistic level, Sirt6 is recruited by forkhead box O (FoxO)3 to the Srebp2 gene promoter where Sirt6 deacetylates histone H3 at lysines 9 and 56, thereby promoting a repressive chromatin state. Remarkably, Sirt6 or FoxO3 overexpression improves hypercholesterolemia in diet-induced or genetically obese mice. In summary, our data suggest an important role of hepatic Sirt6 and FoxO3 in the regulation of cholesterol homeostasis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Rongya
authors.initials: R
authors.lastname: Tao
authors.forename: Xiwen
authors.initials: X
authors.lastname: Xiong
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: X Charlie
authors.initials: XC
authors.lastname: Dong
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D044127:Epigenesis, Genetic; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D037761:Sirtuins / Q000502:physiology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis*
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D006657:Histones; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; C501860:Sirt6 protein, mouse; D037761:Sirtuins
keywords: epigenetics; forkhead box O3 transcription factor; gene regulation; histone acetylation; sirtuin 6; sterol-regulatory element binding protein 2; transcription