Thyroid hormone receptor beta in MASH

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are widespread diseases influenced by thyroid hormone (TH). Hypothyroidism pro-motes hyperlipidemia, obesity, and insulin resistance, while TH replacement therapy and thyromimetics show promising results in improving disease progression. However, recent studies indicate that is not the systemic levels but the local hepatic TH metabolism that plays a crucial role. This is primarily controlled in the liver by the TH beta receptor (TRβ) and TH-activating deiodinase type I (DIO1). In humans, the severity of MASH correlates with reduced hepatic TRβ expression, indicating developing TH resistance, which could therapeutically diminish the efficacy of thyromimetics. This dissertation investigates the role of hepatic TRβ and DIO1 during MASH development. Using TRβ knockout mice and viral overexpression of TRβ, the influence of receptor levels on MASH progression is examined. The experimental approach also included the development of a novel MASH mouse model by combining a choline-deficient high-fat diet with optimized methionine concentration and thermoneutral housing, reflecting important human charac-teristics such as a reduction in TRβ during disease progression. Additionally, in vitro studies with primary mouse hepatocytes were conducted to identify specific factors that can selec-tively modulate deiodinase type 1 or TRβ to find new therapeutic approaches for improving local TH availability. The main results showed that thermoneutrality not only mitigates the usual hyperthyroidism of TRβ knockout mice, allowing the study of TRβ without confounding effects, but also that such a mouse model better reflects the human situation compared to studies at room tem-perature. The lack of TRβ in the animals led to increased fat mass but improved fibrosis and less inflammation, while TRβ overexpression had no effect. Increased Dio1 mRNA after MASH induction indicated a protective compensatory mechanism. The findings clearly demonstrate that a reduction in the TRβ signaling pathway can be beneficial for certain dis-ease pathologies, thus questioning the use of thyromimetics in later stages of fibrosis.