THR-ß agonism improves disease activity and metabolism independent of body weight in a mouse model of non-alcoholic steatohepatitis and fibrosis

Abstract

Background and Purpose: Activation of hepatic thyroid hormone receptor s (THR-s) is associated with systemic lipid lowering, increased bile acid synthesis and fat oxidation. In patients with non-alcoholic steatohepatitis (NASH), treatment with THR-s agonists led to reduction in hepatic steatosis and circulating lipids, and resolution of NASH. We chose resmetirom (MGL-3196), a liver-directed, selective THR-s agonist, as a prototype to investigate the effects of THR-s agonism in mice with diet-induced obesity (DIO) and biopsy-confirmed advanced NASH with fibrosis. Experimental Approach: C57Bl/6J mice were fed a diet high in fat, fructose and cholesterol for 34 weeks, and only biopsy-confirmed DIO-NASH mice with fibrosis were included. Resmetirom was then administered at a daily dose of 3 mg/kg p.o. over a period of eight weeks. Systemic and hepatic metabolic parameters, histological NAFLD activity and fibrosis scores, and liver RNA expression profiles were determined to assess the effect of THR-s agonism. Key Results: Treatment with resmetirom did not influence body weight but led to significant reduction in liver weight (-43 %, p<0.001), hepatic steatosis (-53 %, p<0.001), plasma ALT activity (-49 %, p<0.001), liver and plasma cholesterol (-27 % and -60 %, respectively, p<0.001), and blood glucose (6.3 vs. 7.5 mmol/l, p<0.001). These metabolic effects translated into significant improvement in NAFLD activity score. Moreover, lower alpha-smooth muscle actin content and down-regulation of genes involved in fibrogenesis indicated a decrease in hepatic fibrosis. Conclusion and implications: Our model robustly reflected clinical observations of body weight-independent improvements in systemic and hepatic metabolism including anti-steatotic activity.