title: The Metabolic Regulator Histone Deacetylase 9 Contributes to Glucose Homeostasis Abnormality Induced by Hepatitis C Virus Infection.
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.
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Jizheng
authors.initials: J
authors.lastname: Chen
authors.affiliation: Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhuo
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Chi
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Junqi
authors.initials: J
authors.lastname: Niu
authors.affiliation: Department of Infectious Diseases, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Yang
authors.affiliation: Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China wqian@njmu.edu.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D000818:Animals; D044963:Biopsy, Fine-Needle; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005943:Gluconeogenesis; D019698:Hepatitis C, Chronic / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D008822:Mice, Transgenic; D062793:Occludin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060225:Tetraspanin 28 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006655:Histone Deacetylases; D062793:Occludin; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D012367:RNA, Viral; D012097:Repressor Proteins; D060225:Tetraspanin 28; D000099186:Histone Deacetylase 3; C554798:CD81 protein, human; C085126:FOXO1 protein, human; C568985:OCLN protein, human; C486544:HDAC9 protein, human; C000597251:PCK2 protein, human