Endocrine Abstracts

Background and Aim: Thyroid hormone beta receptor (TRβ) agonists have shown promising results to improve non-alcoholic steatohepatitis in preclinical studies and clinical trials. However, a recent cross-sectional study on human liver biopsies found that TRβ expression decreases during non-alcoholic steatohepatitis (NASH), which may indicate developing thyroid hormone resistance and pose a challenge for TRβ agonists. We aim to study how the changes in TRβ expression impact NASH progression.

Methods: We investigated the alterations of TRβ in two animal models using a novel paradigm that combines choline-deficient high fat diet (CD-HFD) with thermoneutrality housing. To study NASH progression, C57BL/6 wild type or TRβ knockout mice were feed with control or CD-HFD at 4, 8, and 16 weeks. AAV8-mediated hepatocyte-specific TRβ in NASH wild type mice was used as gain-of-function approach. Histology, gene expression, body composition, metabolic parameters and thyroid hormone in serum were measured.

Results: We confirm that TRβ is reduced in mouse NASH, as in humans. Remarkably, treated mice lacking TRβ did not perform worse, but instead showed less liver fibrosis and decreased expression of NASH-associated genes. This effect was not due to the endogenous hyperthyroidism usually observed in TRβ knockout mice, as their thyroid hormone levels normalized at thermoneutrality. On the other hand, increasing TRβ expression in wildtype NASH mice using liver-targeted gene therapy did not result in any improvement in histology, gene expression, or metabolic parameters.

Conclusion: Taken together, our data suggest that downregulation of TRβ expression is not detrimental for NASH progression, and elevating TRβ during NASH without additional ligand does not have beneficial effects on hepatic health or overall metabolism. The findings therefore highlight the importance of targeting local ligand and not receptor availability and suggest that liver-specificity rather than isoform-specificity, might be of greater relevance for NASH treatment.