Lack of thyroid hormone receptor beta is not detrimental for non-alcoholic steatohepatitis progression.

Abstract

Agonists for thyroid hormone receptor β (TRβ) show promise in preclinical studies and clinical trials to improve non-alcoholic fatty liver disease. A recent study on human livers, however, revealed reduced TRβ expression in non-alcoholic steatohepatitis (NASH), indicating a developing thyroid hormone resistance, which could constitute a major obstacle for those agonists. Using a rapid NASH paradigm combining choline-deficient high-fat diet and thermoneutrality, we confirm that TRβ declines during disease progression in mice similar to humans. Contrary to expectations, mice lacking TRβ showed less liver fibrosis, and NASH marker genes were not elevated. Conversely, increasing TRβ expression in wild-type NASH mice using liver-targeted gene therapy did not improve histology, gene expression, or metabolic parameters, indicating that TRβ receptor levels are of minor relevance for NASH development and progression in our model, and suggest that liver-rather than isoform-specificity might be more relevant for NASH treatment with thyroid hormone receptor agonists.

• Authors: Nuria Lopez-Alcantara, Rebecca Oelkrug, Sarah Christine Sentis, Henriette Kirchner, Jens Mittag
• Journal: iScience (iScience) Vol. 26 Issue 10 Pg. 108064 (Oct 20 2023) ISSN: 2589-0042 [Electronic] United States
• PMID: 37822510 (Publication Type: Journal Article)
• Copyright: © 2023 The Author(s).