Extrahepatic effects of thyroid hormone and resmetirom override their beneficial hepatic effects in alcohol-associated liver disease in mice
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Background
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. Hepatic thyroid hormone (TH) action or liver-specific thyromimetics, e.g. resmetirom, can reduce hepatic triglycerides. We therefore hypothesized that TH treatment could ameliorate ALD.
Methods
To induce ALD, 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. The liquid diets were supplemented with solvent, T3 or Resmetirom. We studied WT and hepatocyte-specific TRβ KO mice (hepTRβKO). Effects were measured by clinical chemistry, liver staining, hepatic triglyceride content, and RNA-sequencing.
Results
Surprisingly, resmetirom had no beneficial effect and T3 treatment even aggravated EtOH-induced steatosis (increased liver weight and hepatic triglycerides). The liver phenotype was worsened in hepTRβKO mice, which still suggested beneficial effects of hepatic TRβ signaling in WT mice. These seemingly paradoxical results could be explained by extrahepatic effects in WAT: WAT weight and adipocyte size were reduced by EtOH, T3 and resmetirom. These data indicate lipolysis and subsequent fatty acid accumulation in the liver, explaining the more severe ALD phenotype with T3 and attenuated effect of resmetirom. As WAT loss was reduced in hepTRβKO mice, the hepatic TRβ mediated the extrahepatic effects of T3 and resmetirom on WAT.
Conclusion
We conclude that extrahepatic TH effects in WAT were detrimental in ALD and counteracted beneficial local hepatic TH/TRβ action. As WAT loss appeared to originate from the hepatic TRβ, this also applied to resmetirom.
