Abstract
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.
Original language | English (US) |
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Pages (from-to) | 2745-2753 |
Number of pages | 9 |
Journal | Journal of lipid research |
Volume | 54 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2013 |
Keywords
- Epigenetics
- Forkhead box O3 transcription factor
- Gene regulation
- Histone acetylation
- Sirtuin 6
- Sterol-regulatory element binding protein 2
- Transcription
ASJC Scopus subject areas
- Biochemistry
- Endocrinology
- Cell Biology