Deletion of Mitogen-inducible gene-6 (Mig6) in the Liver Alters Glucose Homeostasis and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Progression

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of chronic liver disease that can progress from benign steatosis to metabolic dysfunction-associated steatohepatitis (MASH) - both of which, if left untreated, can progress to cirrhosis and hepatocellular carcinoma. The strongest risk factor for progression of MASLD to MASH is insulin resistance. Previous work in our lab identified that the adaptor protein mitogen-inducible gene-6 (Mig6) is increased in obese mice and that deletion of Mig6 in the liver (LKO) improves glucose tolerance and insulin action during hyperinsulinemic-euglycemic clamps in diet-induced obese mice. Mig6 is an endogenous feedback inhibitor of epidermal growth factor receptor activation (EGFR) and regulates cellular repair and survival. Thus, we sought to elucidate the extent to which loss of Mig6 modulates the progression of MASLD to MASH. We hypothesized that liver-specific loss of Mig6 during early MASLD improves whole-body glucose homeostasis and protects against MASLD-mediated liver damage. LKO mice and matched, control littermates (CON) were fed a MASH diet (40% fat, 40% carbohydrate, 2% cholesterol; CON n=13-19, LKO n=16-22) or a low-fat-matched diet (LFD; 10% fat, 70% carbohydrate; CON n=8-16, LKO n=16-21) for up to 40 weeks. Body weights were recorded weekly, and body composition assessment, glucose and insulin tolerance tests, and hepatic histological analysis were performed after 20-, 30- and 40-weeks on each diet. Compared to the MASH-fed CON mice, MASH-fed LKO mice had lower body weights starting at 10-weeks and persisting throughout the study. Body composition analysis established these differences in body weight were due to decreases in fat, but not lean, mass. Interestingly, whereas intraperitoneal glucose tolerance tests did not identify significant differences in glucose handling between the LFD and MASH fed mice, oral glucose tolerance was significantly improved in 10- and 20-week MASH-fed LKO mice, suggesting alterations in the incretin response in this MASH model. Lastly, histological analysis revealed MASH-fed LKO mice had a preservation of hepatic lipid zonation and blunted levels of circulating alanine aminotransferase (ALT) compared to MASH-fed CON, indicating less hepatic damage in LKO mice. These results suggest that liver-specific loss of Mig6 improves whole-body glucose handling, which in turn ameliorates hepatic damage during MASLD progression. In conclusion, Mig6 prevents, or at least delays, the progression of MASLD, which may reveal a new therapeutic area for the prevention and treatment of MASH. MS was supported by a National Cancer Institute Cancer Metabolism Training Program Postdoctoral Fellowship (T32CA221709). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.