Jung-Yoon Yoo1, Tae Hoon Kim1, Sieun Kong2, Ju Hee Lee2, Wonseok Choi3, Koon Soon Kim2, Hyun Jin Kim2, Jae-Wook Jeong1, Bon Jeong Ku2. 1. Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, Michigan, USA. 2. Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea. 3. Department of Food Science and Technology, Korea National University of Transportation, Chungju, Korea.
Abstract
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 (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. RESULTS: 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. 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.
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 (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, humanhepatocellular 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-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. 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.
Authors: Byung Kil Park; Eun-Ah Lee; Hee-Youn Kim; Jun Choul Lee; Koon Soon Kim; Won Hoon Jeong; Ki Young Kim; Bon Jeong Ku; Sang Dal Rhee Journal: J Diabetes Res Date: 2016-12-07 Impact factor: 4.011
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