Histone methyltransferase G9a modulates hepatic insulin signaling via regulating HMGA1

Publication date: February 2018 Source:Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 2 Author(s): Weili Xue, Jin Huang, Hong Chen, Yu Zhang, Xiuqin Zhu, Jianshuang Li, Wenquan Zhang, Yangmian Yuan, Yan Wang, Ling Zheng, Kun Huang Hepatic insulin sensitivity is critical for glucose homeostasis, and insulin resistance is a fundamental syndrome found in various metabolic disorders, including obesity and type 2 diabetes. Despite considerable studies on the mechanisms of hepatic insulin resistance, the link between epigenetic regulation and the development of insulin resistance remains elusive. Here, we reported that G9a/EHMT2, a histone methyltransferase, was markedly decreased in the liver of db/db mice and high-fat diet (HFD)-fed mice. In cultured hepatic cells, G9a knockdown resulted in downregulation of insulin receptor, p-AKT and p-GSK3β; while upon upregulation, G9a prevented the palmitic acid- or glucosamine-induced insulin resistance by preserving the normal level of insulin receptor and integrity of insulin signaling. Further mechanistic study suggested that G9a regulated the expression level of high mobility group AT-hook 1 (HMGA1), a key regulator responsible for the transcription of insulin receptor (INSR) gene. Overexpression of HMGA1 normalized the impaired insulin signaling in G9a knockdown hepatic cells. Importantly, in db/db mice, restoring the expression level of G9a not only upregulated HMGA1 level and improv...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research