loading page

THR-ß agonism improves disease activity and metabolism independent of body weight in a mouse model of non-alcoholic steatohepatitis and fibrosis
  • +3
  • Aimo Kannt,
  • Paulus Wohlfart,
  • Andreas Madsen,
  • Sanne Veidal,
  • Michael Feigh,
  • Dieter Schmoll
Aimo Kannt
Sanofi-Aventis Deutschland GmbH
Author Profile
Paulus Wohlfart
Sanofi-Aventis Deutschland GmbH
Author Profile
Andreas Madsen
Gubra
Author Profile
Sanne Veidal
Gubra
Author Profile
Michael Feigh
Gubra
Author Profile
Dieter Schmoll
Sanofi-Aventis Deutschland GmbH
Author Profile

Abstract

Background and Purpose: Activation of hepatic thyroid hormone receptor ß (THR-ß) is associated with systemic lipid lowering, increased bile acid synthesis and fat oxidation. In patients with non-alcoholic steatohepatitis (NASH), treatment with THR-ß agonists led to reduction in hepatic steatosis and circulating lipids, and resolution of NASH. We chose resmetirom (MGL-3196), a liver-directed, selective THR-ß agonist, as a prototype to investigate the effects of THR-ß 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-ß 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.

Peer review status:IN REVISION

27 Apr 2020Submitted to British Journal of Pharmacology
28 Apr 2020Submission Checks Completed
28 Apr 2020Assigned to Editor
19 May 2020Reviewer(s) Assigned
10 Aug 2020Review(s) Completed, Editorial Evaluation Pending
24 Aug 2020Editorial Decision: Revise Minor
18 Sep 20201st Revision Received
21 Sep 2020Assigned to Editor
21 Sep 2020Submission Checks Completed