Role of Mig-6 in hepatic glucose metabolism

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.

To investigate Mig-6 functioning in the liver, we used conditionally ablated Mig-6 using the Albumin-Cre mouse model (Alb(cre/+) Mig-6(f/f) ; Mig-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-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.

Serum fasting glucose levels were significantly higher in Mig-6(d/d) versus Mig-6(f/f) mice. On an insulin tolerance test, insulin sensitivity was decreased in Mig-6(d/d) versus Mig-6(f/f) mice. Furthermore, hepatic expression of the glucokinase (Gck), glucose-6-phosphatase (G6pc), and phosphoenolpyruvate carboxykinase 1 (Pck1) genes was decreased significantly in Mig-6(d/d) mice. Phosphorylation of EGFR, ERK1/2, AKT, mTOR, JNK, and IRS-1 was increased in Mig-6(d/d) compared with Mig-6(f/f) mice.

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.