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 Charlie Dong

doi:10.1074/jbc.m113.481473

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 LDL-cholesterol 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.

Highlights

proprotein convertase subtilisin kexin type 9 (PCSK9) is critical for LDL-cholesterol regulation, but the epigenetic regulation of the PCSK9 gene is not clear
To examine which lipoprotein-associated cholesterol might be modulated by Sirt6, we analyzed cholesterol in HDL and LDL/VLDL fractions of sera from control floxed (LoxpT6) and Sirt6 liver-specific knock-out mice (LKOT6)
The results showed that Sirt6 was highly enriched at the 5Ј-untranslated region (UTR) of the Pcsk9 gene, and H3K9 and H3K56 acetylation levels were dramatically decreased in Sirt6 overexpressed hepatocytes (Fig. 5, A and B)

Summary

Introduction

PCSK9 is critical for LDL-cholesterol regulation, but the epigenetic regulation of the PCSK9 gene is not clear. Results: FoxO3 and Sirt suppress the PCSK9 gene expression and reduce LDL-cholesterol. Conclusion: Hepatic FoxO3 and Sirt control LDL-cholesterol homeostasis. Proper control of LDL-cholesterol homeostasis is critical for organismal health. In this work we have discovered that Sirt, an NAD؉-dependent histone deacetylase, plays a critical role in the regulation of the Pcsk gene expression in mice. Hepatic Sirt deficiency leads to elevated Pcsk gene expression and LDL-cholesterol as well. We have demonstrated that Sirt can be recruited by forkhead transcription factor FoxO3 to the proximal promoter region of the Pcsk gene and deacetylates histone H3 at lysines 9 and 56, thereby suppressing the gene expression. Our data suggest that FoxO3 and Sirt, two longevity genes, can reduce LDL-cholesterol levels through regulation of the Pcsk gene

Methods

Results

Conclusion