Role of Mig-6 in hepatic glucose metabolism

Background Mitogen‐inducible gene 6 (Mig‐6) has an important role in the regulation of cholesterol homeostasis and bile acid synthesis. However, the physiological functions of Mig‐6 in the liver remain poorly understood. Methods To investigate Mig‐6 functioning in the liver, we used conditionally ablated Mig‐6 using the Albumin‐Cre mouse model (Albcre/+Mig‐6f/f; Mig‐6d/d). Male mice were killed after a 24‐h fast and refed after 24 h fasting. Fasting glucose and insulin levels were measured and western blot analyses were performed to determine epidermal growth factor receptor (EGFR), extracellular signal‐regulated kinase (ERK) 1/2, AKT, mammalian target of rapamycin (mTOR), c‐Jun N‐terminal kinase (JNK), and Insulin receptor substrate‐1 (IRS‐1) in liver tissue samples. In addition, human hepatocellular carcinoma HepG2 cells were transfected with Mig‐6 short interference (si) RNA before western blot analysis. Results Serum fasting glucose levels were significantly higher in Mig‐6d/d versus Mig‐6f/f mice. On an insulin tolerance test, insulin sensitivity was decreased in Mig‐6d/d versus Mig‐6f/f mice. Furthermore, hepatic expression of the glucokinase (Gck), glucose‐6‐phosphatase (G6pc), and phosphoenolpyruvate carboxykinase 1 (Pck1) genes was decreased significantly in Mig‐6d/d mice. Phosphorylation of EGFR, ERK1/2, AKT, mTOR, JNK, and IRS‐1 was increased in Mig‐6d/d compared with Mig‐6f/f mice. Conclusion Liver‐specific ablation of Mig‐6 caused hyperglycemia by hepatic insulin resistance. Increased EGFR signaling following Mig‐6 ablation activated JNK and eventually induced insulin resistance by increasing phosphorylation of IRS‐1 at serine 307. This is the first report of Mig‐6 involvement in hepatic insulin resistance and a new mechanism that explains hepatic insulin resistance. 摘要 背景 有丝分裂原诱导基因(Mitogen‐inducible gene 6,Mig‐6)具有重要的调节胆固醇动态平衡以及胆汁酸合成的作用。然而,目前我们仍然对Mig‐6在肝脏的生理功能知之甚少。 方法 为了调查Mig‐6在肝脏的功能,我们在Albumin‐Cre小鼠模型(Albcre/+Mig‐6f/f;Mig‐6d/d)中有条件地敲除了Mig‐6。雄性小鼠禁食24小时后再恢复喂食,之后再处死。测定了空腹血糖与胰岛素水平,并且使用western blot分析法测定了肝组织样本中的表皮生长因子受体(determine epidermal growth factor receptor,EGFR)、细胞外信号调节激酶(extracellular signal‐regulated kinase,ERK)1/2、AKT、哺乳动物雷帕霉素靶蛋白(mammalian target of Rapamycin,mTOR)、c‐Jun氨基末端激酶(c‐Jun N‐terminal kinase,JNK)以及胰岛素受体底物‐1(Insulin receptor substrate‐1,IRS‐1)。另外,在进行western blot分析之前还使用Mig‐6短干扰(si)RNA来转染人类肝细胞癌HepG2细胞。 结果 与Mig‐6f/f小鼠相比,Mig‐6d/d小鼠的血清空腹血糖水平显著更高。在胰岛素耐量试验中,与Mig‐6f/f小鼠相比,Mig‐6d/d小鼠的胰岛素敏感性下降了。此外,在Mig‐6d/d小鼠中,肝脏表达的葡萄糖激酶、葡萄糖‐6‐磷酸酶以及磷酸烯醇式丙酮酸