The Metabolic Regulator Histone Deacetylase 9 Contributes to Glucose Homeostasis Abnormality Induced by Hepatitis C Virus Infection
The Metabolic Regulator Histone Deacetylase 9 Contributes to Glucose Homeostasis Abnormality Induced by Hepatitis C Virus Infection
复制标题
代谢调节剂组蛋白脱乙酰酶 9 导致丙型肝炎病毒感染引起的血糖稳态异常
DOI：
10.2337/db15-0197
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发表时间：
2015-12-01
期刊：
影响因子：
7.7
通讯作者：
Chen, Xinwen
中科院分区：
文献类型：
--
作者：
Chen, Jizheng;Wang, Ning;Chen, Xinwen
IIa 类组蛋白脱乙酰酶 (HDAC)，例如 HDAC4、HDAC5 和 HDAC7，提供调节葡萄糖稳态的关键机制。在此，我们报道 HDAC9（另一种 IIa 类 HDAC）通过 Forkhead box O (FoxO) 家族转录因子 FoxO1 与 HDAC3 的脱乙酰化来调节肝脏糖异生。具体而言，HDAC9 表达在丙型肝炎病毒（HCV）感染后会被强烈诱导。 HCV 诱导的 HDAC9 上调通过促进糖异生基因（包括磷酸烯醇丙酮酸羧激酶和葡萄糖 6-磷酸酶）的表达来增强糖异生，表明 HDAC9 在 HCV 相关的过度糖异生反应的发展中发挥着重要作用。此外，HCV 感染患者和持续性 HCV 感染小鼠的肝脏中 HDAC9 表达水平和糖异生活性升高，强调了这些结果的临床相关性。我们的结果表明 HDAC9 参与葡萄糖代谢、HCV 诱导的葡萄糖稳态异常和 2 型糖尿病。
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.