Diet‐Induced Obesity and Hepatic ER Stress Increase Mig6 and Dampen EGFR Activity

Hepatocytes maintain a regenerative capacity and undergo proliferation following injury or loss of liver tissue. Complete regeneration requires growth factors, such as epidermal growth factor (EGF). Indeed, both the EGF ligand and receptor (EGFR) expression and activity are increased following a partial hepatectomy. Moreover, EGFR is required for full liver regeneration. However, EGFR expression and activity are dampened in genetic models of obesity‐induced diabetes, and obesity dampens complete hepatic regeneration in genetic and diet‐induced obesity (DIO) and diabetes. Therefore, restoring EGFR activation under DIO could restore liver regeneration. As an inducible feedback inhibitor of EGFR, mitogen‐inducible gene 6 (Mig6) is a novel target for enhancing liver regeneration under DIO. Thus, we hypothesized hepatic stress induces Mig6 expression and causes dampened EGFR activation during DIO. Using C57Bl/6 mice fed a high fat diet we identified Mig6 expression was increased during DIO and hepatic endoplasmic reticulum (ER) stress. Furthermore, both chemical and fatty acid driven ER stress increased Mig6 expression and decreased EGF‐mediated EGFR activation in primary rat hepatocytes and cell lines. Additionally, adenoviral‐mediated Mig6 overexpression decreased EGF‐mediated EGFR activation. Finally, liver mass was increased in liver‐specific Mig6 knockout mice compared to wild‐type controls, suggesting Mig6 restricts hepatic growth. We conclude Mig6 is increased during ER stress from DIO and may reduce EGFR activation. The implications are the induction of Mig6 during DIO may attenuate liver regeneration and repair.