Dysregulation of hepatic deiodinase type I in metabolically associated steatotic liver disease.

Hepatic thyroid hormone action plays an important role in preventing the development and progression of metabolic liver diseases, as evidenced by the recent success of the receptor-specific agonist resmetirom. The liver enzyme deiodinase type I (DIO1) is important for controlling the local availability of thyroid hormone and is upregulated in metabolically associated steatotic liver disease (MASLD), which is thought to be a compensatory mechanism to enhance local hormone action. However, it remains unclear whether this increase is maintained in later stages of MASLD and whether an induction of Dio1 can provide beneficial metabolic effects. Studying mouse models with different stages of MASLD, we show here that Dio1 mRNA expression and activity are rapidly induced within 1 week by high-caloric dietary intervention. In later stages, this increase was less pronounced. Surprisingly, altered Dio1 mRNA concentration became progressively less well associated with altered DIO1 enzyme activity, suggesting uncoupling of mRNA and protein biosynthesis. In order to enhance DIO1 activity in MASLD development, a transgenic strategy was applied by using an adeno-associated virus-based liver-specific gene therapy with either the Dio1 or Socs3 gene. In either model, DIO1 activity was increased, but neither thyroid hormone target genes nor metabolic parameters were positively affected in the time frame of the experiment. We conclude that hepatic DIO1 biosynthesis becomes progressively disturbed with disease progression in MASLD by a decoupling of its transcript and protein levels, highlighting the key importance of translational processes controlling DIO1 in hepatocytes, which are likely affected by local inflammatory mechanisms.