Hepatic thyroid hormone signalling in alcohol-associated liver disease

Alcohol-associated liver disease (ALD) is a common type of liver disease worldwide. Excessive consumption of ethanol (EtOH) causes fat accumulation leading to hepatic steatosis. As the liver disease progresses, it becomes more severe due to hepatocyte dysfunction, subsequent inflammation and fibrosis. Hepatic thyroid hormone (TH) action via systemic triiodothyronine (T3) or liver-specific thyromimetics can reduce hepatic triglycerides and stimulate hepatocyte proliferation. TH receptors (TR) therefore represent a potential therapeutic target in liver diseases that regulate hepatic metabolic processes and may determine the outcome of ALD. We hypothesised that TH treatment could ameliorate ALD. Therefore, we aimed to determine the distinct roles of TH and TRβ signalling in ALD in an organ-specific manner. To study ALD, the established NIAAA mouse model was used to induce hepatic steatosis in wildtype (WT), hepatocyte-specific TRβ knockout (hepTRβKO) and hepatocyte-specific TRβ mutant (hepTRβGS) mice. Mice were treated with either EtOH or liquid control diet for 10 days followed by a single EtOH or maltose control gavage on day 11. For TH treatment, the liquid diets were supplemented with solvent, T3 or Resmetirom, a hepatocyte-specific and TRβ-selective antisteatotic thyromimetic to distinguish local hepatic TH/TRβ effects from extrahepatic TH effects. Surprisingly, T3 treatment aggravated EtOH-induced steatosis as evidenced by elevated serum AST and ALT concentrations, increased liver weight and higher hepatic triglycerides. Contrary to the hypothesis, T3 treatment did not protect from ALD. Interestingly, the liver phenotype was worsened in hepTRβKO mice, which suggests beneficial effects of hepatic TH/TRβ signalling in WT mice. HepTRβGS mice showed the same steatotic phenotype as the hepTRβKO mice demonstrating that noncanonical TH signalling does not have a beneficial impact on liver steatosis. Furthermore, RNA-sequencing supported the idea that activated lipid metabolism is beneficial in ALD. The detrimental effect of THs could be attributed to the white adipose tissue (WAT). WAT weight and adipocyte size was enormously reduced by EtOH and T3, indicating lipolysis and subsequent fatty acid accumulation in the liver, explaining the more severe ALD phenotype with T3. Interestingly, these adverse extrahepatic effects were attenuated also by Resmetirom. Activation of WAT confirmed by adipocyte shrinkage and absence of any transcriptional changes compared to T3 resulted in normal liver weight and no accumulation of hepatic triglycerides compared to T3-treated mice due to beneficial intrahepatic TH effects. In conclusion, this study demonstrates that TH treatment in ALD has two very different consequences; the systemic effects of T3 in ALD (WAT shrinkage) are detrimental and counteract the beneficial local hepatic TH/TRβ action, precluding T3 treatment in ALD. Similarly, Resmetirom induces extrahepatic effects in WAT, that may impair its therapeutic potential in ALD. These results suggest the contribution of a hepatokine, that stimulates WAT lipolysis and is regulated by the hepatic TRβ, constituting a novel T3/TRβ-liver-WAT axis. Such extrahepatic TH effects extend the concept of local TH action and require further investigation.