The Metabolic Regulator Histone Deacetylase 9 Contributes to Glucose Homeostasis Abnormality Induced by Hepatitis C Virus Infection

Jizheng Chen; Ning Wang; Mei Dong; Min Guo; Yang Zhao; Zhiyong Zhuo; Chao Zhang; Xiumei Chi; Yu Pan; Jing Jiang; Hong Tang; Junqi Niu; Dongliang Yang; Zhong Li; Xiao Han; Qian Wang; Xinwen Chen

doi:10.2337/db15-0197

The Metabolic Regulator Histone Deacetylase 9 Contributes to Glucose Homeostasis Abnormality Induced by Hepatitis C Virus Infection

Diabetes. 2015 Dec;64(12):4088-98. doi: 10.2337/db15-0197. Epub 2015 Sep 29.

Authors

Jizheng Chen¹, Ning Wang², Mei Dong², Min Guo¹, Yang Zhao³, Zhiyong Zhuo³, Chao Zhang³, Xiumei Chi⁴, Yu Pan⁴, Jing Jiang⁴, Hong Tang¹, Junqi Niu⁴, Dongliang Yang⁵, Zhong Li², Xiao Han², Qian Wang⁶, Xinwen Chen¹

Affiliations

¹ State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
² Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
³ Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁴ Department of Hepatology, The First Hospital of Jilin University, Changchun, China.
⁵ Department of Infectious Diseases, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China wqian@njmu.edu.cn.

PMID: 26420860
DOI: 10.2337/db15-0197

Abstract

Class IIa histone deacetylases (HDACs), such as HDAC4, HDAC5, and HDAC7, provide critical mechanisms for regulating glucose homeostasis. Here we report that HDAC9, another class IIa HDAC, regulates hepatic gluconeogenesis via deacetylation of a Forkhead box O (FoxO) family transcription factor, FoxO1, together with HDAC3. Specifically, HDAC9 expression can be strongly induced upon hepatitis C virus (HCV) infection. HCV-induced HDAC9 upregulation enhances gluconeogenesis by promoting the expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, indicating a major role for HDAC9 in the development of HCV-associated exaggerated gluconeogenic responses. Moreover, HDAC9 expression levels and gluconeogenic activities were elevated in livers from HCV-infected patients and persistent HCV-infected mice, emphasizing the clinical relevance of these results. Our results suggest HDAC9 is involved in glucose metabolism, HCV-induced abnormal glucose homeostasis, and type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Biopsy, Fine-Needle
Cell Line, Tumor
Enzyme Induction
Female
Forkhead Box Protein O1
Forkhead Transcription Factors / metabolism*
Gluconeogenesis*
Hepatitis C, Chronic / blood
Hepatitis C, Chronic / metabolism*
Hepatitis C, Chronic / pathology
Hepatitis C, Chronic / virology
Histone Deacetylases / genetics
Histone Deacetylases / metabolism*
Humans
Insulin Resistance*
Liver / metabolism*
Liver / pathology
Liver / virology
Male
Mice, Transgenic
Occludin / antagonists & inhibitors
Occludin / genetics
Occludin / metabolism
Phosphoenolpyruvate Carboxykinase (ATP) / antagonists & inhibitors
Phosphoenolpyruvate Carboxykinase (ATP) / genetics
Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
Phosphorylation
Protein Processing, Post-Translational
RNA Interference
RNA, Viral / antagonists & inhibitors
RNA, Viral / blood
RNA, Viral / metabolism
Repressor Proteins / antagonists & inhibitors
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Tetraspanin 28 / antagonists & inhibitors
Tetraspanin 28 / genetics
Tetraspanin 28 / metabolism

Substances

CD81 protein, human
FOXO1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
OCLN protein, human
Occludin
RNA, Viral
Repressor Proteins
Tetraspanin 28
HDAC9 protein, human
Histone Deacetylases
histone deacetylase 3
PCK2 protein, human
Phosphoenolpyruvate Carboxykinase (ATP)