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

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

Research output: Contribution to journalArticle

58 Citations (Scopus)

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 languageEnglish
Pages (from-to)2745-2753
Number of pages9
JournalJournal of Lipid Research
Volume54
Issue number10
DOIs
StatePublished - Oct 2013

Fingerprint

Sterol Regulatory Element Binding Protein 2
Biosynthesis
Cholesterol
Hypercholesterolemia
Liver
Homeostasis
Biochemical Phenomena
Genes
Obese Mice
Histones
Lysine
Chromatin
Nutrition
Gene expression
Diet
Health

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
  • Cell Biology
  • Endocrinology

Cite this

Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6. / Tao, Rongya; Xiong, Xiwen; DePinho, Ronald A.; Deng, Chu Xia; Dong, X.

In: Journal of Lipid Research, Vol. 54, No. 10, 10.2013, p. 2745-2753.

Research output: Contribution to journalArticle

Tao, Rongya ; Xiong, Xiwen ; DePinho, Ronald A. ; Deng, Chu Xia ; Dong, X. / Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6. In: Journal of Lipid Research. 2013 ; Vol. 54, No. 10. pp. 2745-2753.
@article{3e931c3afe184e108c01560f9af60fc5,
title = "Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6",
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.",
keywords = "Epigenetics, Forkhead box O3 transcription factor, Gene regulation, Histone acetylation, Sirtuin 6, Sterol-regulatory element binding protein 2, Transcription",
author = "Rongya Tao and Xiwen Xiong and DePinho, {Ronald A.} and Deng, {Chu Xia} and X. Dong",
year = "2013",
month = "10",
doi = "10.1194/jlr.M039339",
language = "English",
volume = "54",
pages = "2745--2753",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "10",

}

TY - JOUR

T1 - Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6

AU - Tao, Rongya

AU - Xiong, Xiwen

AU - DePinho, Ronald A.

AU - Deng, Chu Xia

AU - Dong, X.

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - Epigenetics

KW - Forkhead box O3 transcription factor

KW - Gene regulation

KW - Histone acetylation

KW - Sirtuin 6

KW - Sterol-regulatory element binding protein 2

KW - Transcription

UR - http://www.scopus.com/inward/record.url?scp=84884134120&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884134120&partnerID=8YFLogxK

U2 - 10.1194/jlr.M039339

DO - 10.1194/jlr.M039339

M3 - Article

VL - 54

SP - 2745

EP - 2753

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 10

ER -