Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis.
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.
Kim
Hyun-Seok
HS
Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Xiao
Cuiying
C
Wang
Rui-Hong
RH
Lahusen
Tyler
T
Xu
Xiaoling
X
Vassilopoulos
Athanassios
A
Vazquez-Ortiz
Guelaguetza
G
Jeong
Won-Il
WI
Park
Ogyi
O
Ki
Sung Hwan
SH
Gao
Bin
B
Deng
Chu-Xia
CX
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*
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
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