Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis

Hyun Seok Kim; Cuiying Xiao; Rui Hong Wang; Tyler Lahusen; Xiaoling Xu; Athanassios Vassilopoulos; Guelaguetza Vazquez-Ortiz; Won Il Jeong; Ogyi Park; Sung Hwan Ki; Bin Gao; Chu Xia Deng

doi:10.1016/j.cmet.2010.06.009

Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis

Hyun Seok Kim, Cuiying Xiao, Rui Hong Wang, Tyler Lahusen, Xiaoling Xu, Athanassios Vassilopoulos, Guelaguetza Vazquez-Ortiz, Won Il Jeong, Ogyi Park, Sung Hwan Ki, Bin Gao, Chu Xia Deng

Department of Life Science

Research output: Contribution to journal › Article › peer-review

453 Scopus citations

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 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.

Original language	English
Pages (from-to)	224-236
Number of pages	13
Journal	Cell Metabolism
Volume	12
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2010.06.009
State	Published - 8 Sep 2010

Bibliographical note

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.

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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 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.",

author = "Kim, {Hyun Seok} and Cuiying Xiao and Wang, {Rui Hong} and Tyler Lahusen and Xiaoling Xu and Athanassios Vassilopoulos and Guelaguetza Vazquez-Ortiz and Jeong, {Won Il} and Ogyi Park and Ki, {Sung Hwan} and Bin Gao and Deng, {Chu Xia}",

note = "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. ",

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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.

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Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis

Abstract

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