TY - JOUR
T1 - Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis
AU - Kim, Hyun Seok
AU - Xiao, Cuiying
AU - Wang, Rui Hong
AU - Lahusen, Tyler
AU - Xu, Xiaoling
AU - Vassilopoulos, Athanassios
AU - Vazquez-Ortiz, Guelaguetza
AU - Jeong, Won Il
AU - Park, Ogyi
AU - Ki, Sung Hwan
AU - Gao, Bin
AU - Deng, Chu Xia
N1 - Funding Information:
We thank Drs. E. Mueller, J. Wess, S. Tydlacka, and C. Chisholm for critical reading of the manuscript, and Drs. O. Gavrilova, W. Jou, D. Simon, and C. Li for technical assistance. This work was supported by the intramural Research Program of National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health.
PY - 2010/9/8
Y1 - 2010/9/8
N2 - 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 β 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.
AB - 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 β 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.
UR - http://www.scopus.com/inward/record.url?scp=77956315551&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2010.06.009
DO - 10.1016/j.cmet.2010.06.009
M3 - Article
C2 - 20816089
AN - SCOPUS:77956315551
SN - 1550-4131
VL - 12
SP - 224
EP - 236
JO - Cell Metabolism
JF - Cell Metabolism
IS - 3
ER -