I 类组蛋白去乙酰化酶（HDAC）在肝脏糖异生中的作用。

The role of class I histone deacetylase (HDAC) on gluconeogenesis in liver.

机构信息

Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

出版信息

Biochem Biophys Res Commun. 2011 Jan 7;404(1):166-72. doi: 10.1016/j.bbrc.2010.11.086. Epub 2010 Nov 23.

DOI:10.1016/j.bbrc.2010.11.086

Abstract

Hepatic gluconeogenesis is crucial for glucose homeostasis. Although sirtuin 1 (Sirt1) is implicated in the regulation of gluconeogenesis in the liver, the effects of other histone deacetylases (HDAC) on gluconeogenesis are unclear. The aim of this study was to identify the role of class I HDACs in hepatic gluconeogenesis. In HepG2 cells and the liver of mice, the expressions of phosphoenol pyruvate carboxykinase (PEPCK) and hepatocyte nuclear factor 4α (HNF4α) were significantly decreased by treatment with a newly designed class I HDAC inhibitor, Ky-2. SiRNA knockdown of HDAC1 expression, but not of HDAC2 or HDAC3, in HepG2 cells decreased PEPCK and HNF4α expression. In HepG2 cells, insulin-stimulated phosphorylation of Akt and forkhead box O 1 (FoxO1) was increased by Ky-2. Pyruvate tolerance tests in Ky-2-treated high-fat-diet (HFD)-fed mice showed a marked reduction in blood glucose compared with vehicle-treated HFD mice. These data suggest that class I HDACs increase HNF4α protein expression and the transcriptional activity of FoxO1, followed by the induction of PEPCK mRNA expression and gluconeogenesis in liver.

摘要

肝糖异生对于葡萄糖稳态至关重要。虽然沉默信息调节因子 1（Sirtuin 1，Sirt1）参与了肝脏中糖异生的调节，但其他组蛋白去乙酰化酶（HDAC）对糖异生的影响尚不清楚。本研究旨在确定 I 类 HDAC 在肝糖异生中的作用。在 HepG2 细胞和小鼠肝脏中，新设计的 I 类 HDAC 抑制剂 Ky-2 处理显著降低了磷酸烯醇丙酮酸羧激酶（PEPCK）和肝细胞核因子 4α（HNF4α）的表达。在 HepG2 细胞中，HDAC1 的 siRNA 敲低而非 HDAC2 或 HDAC3 的敲低降低了 PEPCK 和 HNF4α 的表达。在 HepG2 细胞中，Ky-2 增加了胰岛素刺激的 Akt 和叉头框 O1（FoxO1）的磷酸化。与 vehicle 处理的 HFD 小鼠相比，Ky-2 处理的高脂肪饮食（HFD）喂养小鼠的丙酮酸耐量试验显示血糖明显降低。这些数据表明，I 类 HDAC 增加了 HNF4α 蛋白表达和 FoxO1 的转录活性，随后诱导了肝脏中 PEPCK mRNA 的表达和糖异生。