Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6[S]

Journal of Lipid Research

Chu-Xia Deng¹  Xiwen Xiong²  Rongya Tao²  Ronald A. DePinho³  X. Charlie Dong⁴ 

[1] and;Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN;Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX;Genetics of Development and Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, the National Institutes of Health, Bethesda, MD;

关键词: gene regulation;    transcription;    histone acetylation;    epigenetics;    sirtuin 6;    forkhead box O3 transcription factor;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown