Open AccessRole of M ig‐6 in hepatic glucose metabolism
Author(s) -
Yoo JungYoon,
Kim Tae Hoon,
Kong Sieun,
Lee Ju Hee,
Choi Wonseok,
Kim Koon Soon,
Kim Hyun Jin,
Jeong JaeWook,
Ku Bon Jeong
Publication year - 2016
Publication title -
journal of diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.949
H-Index - 43
eISSN - 1753-0407
pISSN - 1753-0393
DOI - 10.1111/1753-0407.12261
Subject(s) - endocrinology , medicine , protein kinase b , glucokinase , phosphoenolpyruvate carboxykinase , insulin receptor , insulin , kinase , biology , insulin resistance , phosphorylation , enzyme , biochemistry
Background Mitogen‐inducible gene 6 ( M ig‐6 ) has an important role in the regulation of cholesterol homeostasis and bile acid synthesis. However, the physiological functions of M ig‐6 in the liver remain poorly understood. Methods To investigate M ig‐6 functioning in the liver, we used conditionally ablated M ig‐6 using the A lbumin‐ C re mouse model ( A lb cre/+ M ig‐6 f/f ; M ig‐6 d/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‐ J un 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 M ig‐6 short interference (si) RNA before western blot analysis. Results Serum fasting glucose levels were significantly higher in M ig‐6 d/d versus M ig‐6 f/f mice. On an insulin tolerance test, insulin sensitivity was decreased in M ig‐6 d/d versus M ig‐6 f/f mice. Furthermore, hepatic expression of the glucokinase ( G ck ), glucose‐6‐phosphatase ( G 6pc ), and phosphoenolpyruvate carboxykinase 1 ( P ck1 ) genes was decreased significantly in M ig‐6 d/d mice. Phosphorylation of EGFR , ERK1 /2, AKT , mTOR , JNK , and IRS ‐1 was increased in M ig‐6 d/d compared with M ig‐6 f/f mice. Conclusion Liver‐specific ablation of M ig‐6 caused hyperglycemia by hepatic insulin resistance. Increased EGFR signaling following M ig‐6 ablation activated JNK and eventually induced insulin resistance by increasing phosphorylation of IRS ‐1 at serine 307. This is the first report of M ig‐6 involvement in hepatic insulin resistance and a new mechanism that explains hepatic insulin resistance.