Stress-activated MIG6 compromises hepatic metabolism during diet-induced obesity

Abstract

Indiana University-Purdue University Indianapolis (IUPUI)Obesity-induced hepatic fat accumulation or nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the United States. Unfortunately, NALFD patients are at higher risk of cardiovascular disease and mortality. The development of hepatic steatosis is multi-factorial and leads to a variety of pathologies. Yet, the molecular mechanisms behind liver disease during hepatic fat accumulation remain unclear. Here, we describe novel mechanisms of impaired liver function in the context of obesity-induced hepatic stress. Using chemical- and fatty acid-induced endoplasmic reticulum (ER) stress, we discovered ER stress decreases the activation of the pro-growth, pro survival, receptor tyrosine kinase, epidermal growth factor receptor (EGFR) in vitro. Importantly, EGFR was inhibited during these stress conditions by the induction and stabilization of mitogen inducible gene 6 (Mig6). Furthermore, Mig6 knockdown in vitro enhanced EGFR signaling and promoted survival. We demonstrated that mice fed a high fat diet have decreased EGFR activation and increased Mig6 protein expression, likely due to obesity-induced ER stress. To determine the functional consequences of increased Mig6 expression, we generated Mig6 liver-specific knockout mice (Mig6 LKO) and subjected them to high fat feeding. During diet-induced obesity, Mig6 LKO mice had improved hepatic glucose tolerance despite no improvements in whole-body insulin sensitivity or insulin secretion. Hepatic insulin signaling, measured by AKT activation, was similar between Mig6 LKO and littermate controls. However, several insulin-sensitive genes involved in gluconeogenesis were altered in Mig6 LKO mice compared to controls. In addition, Mig6 LKO mice had higher plasma high density lipoproteins and triglycerides despite similar liver lipid content. Using RNA sequencing we discovered Mig6 regulates several metabolic pathways in liver. These findings indicated Mig6 not only controls hepatic growth and survival but also regulates metabolism. This work will help us to better understand how augmented growth factor signaling impacts metabolic regulation during pathological obesity