Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6[S]
| Autor: | Rongya Tao, Xiwen Xiong, Ronald A. DePinho, Chu-Xia Deng, X. Charlie Dong |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Journal of Lipid Research, Vol 54, Iss 10, Pp 2745-2753 (2013) |
| Druh dokumentu: | article |
| ISSN: | 0022-2275 87283476 |
| DOI: | 10.1194/jlr.M039339 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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