FoxO3 transcription factor and Sirt6 deacetylase regulate low density lipoprotein (LDL)-cholesterol homeostasis via control of the proprotein convertase subtilisin/kexin type 9 (Pcsk9) gene expression

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

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Elevated LDL-cholesterol is a risk factor for the development of cardiovascular disease. Thus, proper control of LDL-cholesterol homeostasis is critical for organismal health. Genetic analysis has identified PCSK9 (proprotein convertase subtilisin/ kexin type 9) as a crucial gene in the regulation of LDLcholesterol via control of LDL receptor degradation. Although biochemical characteristics and clinical implications of PCSK9 have been extensively investigated, epigenetic regulation of this gene is largely unknown. In this work we have discovered that Sirt6, an NAD+-dependent histone deacetylase, plays a critical role in the regulation of the Pcsk9 gene expression in mice. Hepatic Sirt6 deficiency leads to elevated Pcsk9 gene expression and LDL-cholesterol as well. Mechanistically, we have demonstrated that Sirt6 can be recruited by forkhead transcription factor FoxO3 to the proximal promoter region of the Pcsk9 gene and deacetylates histone H3 at lysines 9 and 56, thereby suppressing the gene expression. Also remarkably, overexpression of Sirt6 in high fat diet-fed mice lowers LDL-cholesterol. Overall, our data suggest that FoxO3 and Sirt6, two longevity genes, can reduce LDL-cholesterol levels through regulation of the Pcsk9 gene.

Original languageEnglish
Pages (from-to)29252-29259
Number of pages8
JournalJournal of Biological Chemistry
Volume288
Issue number41
DOIs
StatePublished - Oct 11 2013

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Proprotein Convertases
Subtilisin
Gene expression
LDL Cholesterol
Homeostasis
Transcription Factors
Gene Expression
Genes
Forkhead Transcription Factors
Histone Deacetylases
LDL Receptors
High Fat Diet
Nutrition
Genetic Promoter Regions
Epigenomics
NAD
Histones
Lysine
Proprotein Convertase 9
Cardiovascular Diseases

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

FoxO3 transcription factor and Sirt6 deacetylase regulate low density lipoprotein (LDL)-cholesterol homeostasis via control of the proprotein convertase subtilisin/kexin type 9 (Pcsk9) gene expression. / Tao, Rongya; Xiong, Xiwen; DePinho, Ronald A.; Deng, Chu Xia; Dong, X.

In: Journal of Biological Chemistry, Vol. 288, No. 41, 11.10.2013, p. 29252-29259.

Research output: Contribution to journalArticle

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