Activation of thyroid hormone receptor-β improved disease activity and metabolism independent of body weight in a mouse model of non-alcoholic steatohepatitis and fibrosis

  • Background and Purpose: Activation of hepatic thyroid hormone receptor β (THR-β) is associated with systemic lipid lowering, increased bile acid synthesis, and fat oxidation. In patients with non-alcoholic steatohepatitis (NASH), treatment with THR-β agonists decreased hepatic steatosis and circulating lipids, and induced resolution of NASH. We chose resmetirom (MGL-3196), a liver-directed, selective THR-β agonist, as a prototype to investigate the effects of THR-β activation 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 administered at a daily dose of 3 mg·kg−1 p.o., for 8 weeks. Systemic and hepatic metabolic parameters, histological non-alcoholic fatty liver disease (NAFLD) activity and fibrosis scores, and liver RNA expression profiles were determined to assess the effect of THR-β activation. Key Results: Treatment with resmetirom did not influence body weight but led to significant reduction in liver weight, hepatic steatosis, plasma alanine aminotransferase activity, liver and plasma cholesterol, and blood glucose. These metabolic effects translated into significant improvement in NAFLD activity score. Moreover, a lower content of α-smooth muscle actin 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.

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Author:Aimo Kannt, Paulus Wohlfart, Andreas Nygaard Madsen, Sanne Skovgård Veidal, Michael Feigh, Dieter Schmoll
URN:urn:nbn:de:hebis:30:3-617819
DOI:https://doi.org/10.1111/bph.15427
ISSN:1476-5381
Parent Title (English):British journal of pharmacology
Publisher:Wiley
Place of publication:Malden, MA
Document Type:Article
Language:English
Date of Publication (online):2021/03/03
Date of first Publication:2021/03/03
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/07/26
Tag:NASH; liver fibrosis; non-alcoholic steatohepatitis; resmetirom; thyroid hormone receptor
Volume:178
Issue:12
Page Number:12
First Page:2412
Last Page:2423
HeBIS-PPN:484037242
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0