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

Rongya Tao, Xiwen Xiong, Ronald A. DePinho, Chu Xia Deng, X. Charlie Dong

Research output: Contribution to journalArticle

84 Scopus citations


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 languageEnglish (US)
Pages (from-to)2745-2753
Number of pages9
JournalJournal of Lipid Research
Issue number10
StatePublished - Oct 1 2013


  • Epigenetics
  • Forkhead box O3 transcription factor
  • Gene regulation
  • Histone acetylation
  • Sirtuin 6
  • Sterol-regulatory element binding protein 2
  • Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

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