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. HCVinduced 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.

Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

“…After adopting more stringent criteria of statistical significance, still a large number of methylated sites were significantly associated with NASH. Among those, there was differential methylation at genes involved in cholesterol transport and inflammation (ARL4C, encoding ADP-ribosylation factor-like 4C), 21,22 glucose metabolism and epigenetics (HDAC9, encoding histone deacetylase 9), 23 liver inflammation and coronary artery disease (COL4A1, encoding collagen, type IV, a 1), 24,25 and liver fibrogenesis (SEMA3E, encoding class 1 semaphorin and ITGB4, encoding integrin b 4 subunit, which is a receptor for laminins). 26,27 These observations may reflect, at the epigenetic level, the presence of hepatic inflammation in NASH and the liver fibrosis contributing to the progression of the disease, 1 in addition to disturbances in cholesterol transport that may participate in NAFLD progression 28 and the increased risk of cardiovascular disease.…”

Sodium butyrate reduces insulin-resistance, fat accumulation and dyslipidemia in type-2 diabetic rat: A comparative study with metformin

“…The histone deacetylases (HDACs) and histone acetyltransferases (HATs) maintain the cellular acetylation and chromatin stability thereby modulate the expression of several genes [2,3]. Further, HDACs play a pivotal role in the pathogenesis of type-2 diabetes due to their important role in lipid and glucose metabolism [4,5]. Additionally, several experimental studies with HDAC inhibitors are highlighted that HDACs and associated mechanisms contributed in the insulin-resistance and beta-cell failure [6e8].…”

Role of HDAC9-FoxO1 Axis in the Transcriptional Program Associated with Hepatic Gluconeogenesis

“…Previous studies have indicated that HCV promotes hepatic gluconeogenesis 13, 16 . To gain insight into the metabolic signature associated with this phenomenon, we examined the influence of HCV infection on the metabolites involved in carbohydrate metabolism and energy pathways from HCV-infected cells using NMR analysis (Supplementary Table S1).…”

“…Among them, class IIa HDACs (HDAC4, 5, 7) are hormone-activated regulators of FoxO and mammalian glucose homeostasis 12 . Our recent studies have indicated that HDAC9, another class IIa HDAC, regulates hepatic gluconeogenesis via deacetylation of FoxO1 together with HDAC3 13 .…”

“…HCV infection per se is associated with insulin resistance in the target pathways of endogenous glucose production and total body glucose disposal 15 . We have reported that chronic HCV infection may induce HDAC9 expression, resulting in an exaggerated gluconeogenic response likely mediated by FoxO1 transcription factor activity, directly predisposing the host to abnormal glucose metabolism 13 .…”