Fatty Liver and Insulin Resistance in the Liver-Specific Knockout Mice of Mitogen Inducible Gene-6.

Byung Kil Park,Eun-Ah Lee,Koon Soon Kim,Hee-Youn Kim,Bon Jeong Ku,Sang Dal Rhee,Won Hoon Jeong,Jun Choul Lee,Ki Young Kim

doi:10.1155/2016/1632061

Abstract

Mitogen inducible gene-6 (Mig-6) is a feedback inhibitor of epidermal growth factor receptor (EGFR) signaling pathway. The liver-specific knockout mice of the Mig-6 gene (Mig-6d/d) showed hepatomegaly and increased hypercholesterolemia. In this study, the biomarkers of insulin resistance and the effects of high-fat diets in the wild (Mig-6f/f) and Mig-6d/d mice were analyzed. The fasting plasma concentrations of glucose, triglyceride, cholesterols, free fatty acids, and HOMA-IR were measured and the glucose tolerance and insulin resistance tests were performed in the 25-week-old Mig-6f/f and the Mig-6d/d mice. The protein levels of active insulin receptor, glucose 6-phosphatase, and phosphoenolpyruvate carboxykinase were analyzed in the liver and fat. The fasting plasma cholesterol and glucose concentration were higher in the Mig-6d/d mice than the Mig-6f/f mice with increased fat deposition in the liver. But the Mig-6d/d mice had the improved glucose intolerance and insulin resistance without increased amount of phosphoinsulin receptor after insulin infusion in the liver. The hepatic concentration of phosphoenolpyruvate carboxykinase was increased in fasting Mig-6d/d mice. The feeding of high-fat diet accelerated the plasma lipids profiles and HOMA-IR in the Mig-6d/d mice but had no differential effects in oral glucose tolerance test and insulin tolerance test in both genotypes. These results suggest that the activated EGFR signaling might increase the fasting plasma glucose concentration through inducing the hepatic steatosis and the improved whole-body insulin resistance in the KO mice be caused by decreased adipogenesis in fat tissues.

Highlights

Mitogen inducible gene-6 (Mig-6) is an adaptor protein that is highly expressed in the liver and kidney [1]
According to Ku et al, liver-specific knockout mice of Mig-6 revealed hepatomegaly and hypercholesterolemia, suggesting that epidermal growth factor receptor (EGFR) signaling pathway or Mig-6 protein in the liver might play an important role in metabolism of lipids [16]
The diabetes-related biomarkers such as plasma concentration of glucose and several lipids and insulin resistance index were analyzed in the wild (Mig-6f/f) and KO (Mig-6d/d) mice at 25 weeks of age

Summary

Introduction

Mitogen inducible gene-6 (Mig-6) is an adaptor protein that is highly expressed in the liver and kidney [1]. The decreased expression of Mig-6 was observed in human breast cancer, which is correlated with reduced overall survival of breast cancer patients [8], and loss of the protein’s function contributes to initiation of several cancers such as lung cancer [5]. The EGFR signaling pathway is activated by binding of ligands, EGF, or TGF-α which is closely associated with cancer [9]. Treatment of an EGFR inhibitor (PD153035) improves glucose intolerance and insulin sensitivity and reduces inflammation in diet-induced obese (DIO) mice [15], indicating the some roles of the EGFR signaling pathway in the pathophysiologies of diabetes mellitus. We analyzed the diabetes mellitus-related biomarkers of liver-specific knockout mice of Mig-6 (Mig-6d/d) and the effects of high-fat diet on the phenotypes

Materials and Methods

Results

Discussion