title: Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis.
abstract: Under various conditions, mammals have the ability to maintain serum glucose concentration within a narrow range. SIRT1 plays an important role in regulating gluconeogenesis and fat metabolism; however, the underlying mechanisms remain elusive. Here, we show that SIRT1 forms a complex with FOXO3a and NRF1 on the SIRT6 promoter and positively regulates expression of SIRT6, which, in turn, negatively regulates glycolysis, triglyceride synthesis, and fat metabolism by deacetylating histone H3 lysine 9 in the promoter of many genes involved in these processes. Liver-specific deletion of SIRT6 in mice causes profound alterations in gene expression, leading to increased glycolysis, triglyceride synthesis, reduced beta oxidation, and fatty liver formation. Human fatty liver samples exhibited significantly lower levels of SIRT6 than did normal controls. Thus, SIRT6 plays a critical role in fat metabolism and may serve as a therapeutic target for treating fatty liver disease, the most common cause of liver dysfunction in humans.
authors.affiliation: Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Cuiying
authors.initials: C
authors.lastname: Xiao
authors.forename: Rui-Hong
authors.initials: RH
authors.lastname: Wang
authors.forename: Tyler
authors.initials: T
authors.lastname: Lahusen
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
authors.forename: Guelaguetza
authors.initials: G
authors.lastname: Vazquez-Ortiz
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ki
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000096:biosynthesis*
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D006657:Histones; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D014280:Triglycerides; C501860:Sirt6 protein, mouse; C516592:SIRT6 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins
references.citation: J Biol Chem. 2005 Jun 3;280(22):21313-20
references.pmid: 15795229
references.citation: Nature. 2008 Nov 13;456(7219):269-73
references.pmid: 18849969
references.citation: Science. 2004 Mar 26;303(5666):2011-5
references.pmid: 14976264
references.citation: Cancer Cell. 2008 Oct 7;14(4):312-23
references.pmid: 18835033
references.citation: IUBMB Life. 2008 Dec;60(12):790-7
references.pmid: 18709650
references.citation: FEBS Lett. 2008 Mar 5;582(5):543-8
references.pmid: 18242175
references.citation: Nature. 2009 Jul 30;460(7255):587-91
references.pmid: 19641587
references.citation: Cancer Cell. 2010 Jan 19;17(1):41-52
references.pmid: 20129246
references.citation: Diabetes Obes Metab. 2009 Mar;11(3):188-95
references.pmid: 18564173
references.citation: Curr Opin Hematol. 2008 Jul;15(4):326-31
references.pmid: 18536570
references.citation: Nature. 2008 Mar 27;452(7186):492-6
references.pmid: 18337721
references.citation: Plant Sci. 2001 May;160(6):1107-1114
references.pmid: 11337067
references.citation: Science. 2004 Dec 17;306(5704):2105-8
references.pmid: 15604409
references.citation: Mol Cell Biol. 2007 Mar;27(5):1881-8
references.pmid: 17210641
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52
references.pmid: 18794531
references.citation: Science. 2005 Oct 14;310(5746):314-7
references.pmid: 16224023
references.citation: Oncogene. 2007 Aug 13;26(37):5489-504
references.pmid: 17694089
references.citation: Cell Metab. 2009 Apr;9(4):327-38
references.pmid: 19356714
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7324-9
references.pmid: 10377413
references.citation: Liver Int. 2007 Jun;27(5):708-15
references.pmid: 17498258
references.citation: Annu Rev Biochem. 2004;73:417-35
references.pmid: 15189148
references.citation: J Lipid Res. 1999 Nov;40(11):2134-9
references.pmid: 10553017
references.citation: Cell. 2009 Jan 9;136(1):62-74
references.pmid: 19135889
references.citation: Int J Biol Sci. 2008 Sep 05;4(5):291-9
references.pmid: 18781224
references.citation: Genesis. 2001 May;30(1):1-6
references.pmid: 11353511
references.citation: Nature. 2000 Nov 9;408(6809):255-62
references.pmid: 11089983
references.citation: Genes Dev. 2006 Nov 1;20(21):2913-21
references.pmid: 17079682
references.citation: Biochem Pharmacol. 1978;27(23):2683-8
references.pmid: 728223
references.citation: Biochem J. 2006 Dec 1;400(2):327-35
references.pmid: 16886907
references.citation: Mol Cell. 2008 Oct 10;32(1):11-20
references.pmid: 18851829
references.citation: Cell Cycle. 2009 Aug 15;8(16):2662-3
references.pmid: 19597350
references.citation: Gastroenterology. 2004 Dec;127(6):1798-808
references.pmid: 15578517
references.citation: Nature. 2005 Mar 3;434(7029):113-8
references.pmid: 15744310
references.citation: Cell. 2004 Feb 20;116(4):551-63
references.pmid: 14980222
references.citation: Cell Metab. 2008 Mar;7(3):227-35
references.pmid: 18316028
references.citation: Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):644-9
references.pmid: 14715643
references.citation: Int J Biol Sci. 2009;5(2):147-52
references.pmid: 19173036
references.citation: J Clin Invest. 2008 Mar;118(3):829-38
references.pmid: 18317565
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12861-6
references.pmid: 17646659
references.citation: Nature. 2007 Nov 15;450(7168):440-4
references.pmid: 18004385
references.citation: Cell. 2010 Jan 22;140(2):280-93
references.pmid: 20141841
references.citation: Cell Cycle. 2009 Aug 15;8(16):2664-6
references.pmid: 19625767
references.citation: Cell. 2006 Jan 27;124(2):315-29
references.pmid: 16439206
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5860-5
references.pmid: 8650183
references.citation: J Intern Med. 2008 Feb;263(2):128-41
references.pmid: 18226091