Background Recent clinical studies suggest that thyroid hormone (TH) and its analogs are beneficial for treatment of non-alcoholic fatty liver disease (NAFLD). TH stimulates β-oxidation of fatty acids and decreases triglyceride (TG) content in the liver (steatosis). Previous evidence suggests progression of NAFLD is characterized by low intrahepatic TH levels possibly regulated by hepatic deiodinase type 1 (Dio1), converting the serum abundant T4 to the bioactive T3 within the liver. We investigated these changes in TH metabolism during the progression of disease to indicate with which drug and at which stage of disease this treatment is most beneficial.

Methods We investigated TH metabolism in mice fed a western diet with fructose (WDF), a dietary model of NAFLD. Liver TH concentrations (T₄ and bioactive T₃) were measured by LC-MS/MS. Deiodinase 1 (Dio1) and 3 (Dio3) activity was measured by conversion of ¹²⁵I-labelled rT₃ and T₃respectively. In a second experiment Dio1 shRNA under an albumin promotor was injected by tail vein to selectively knockdown Dio1 (Dio1 KD) in the liver of WDF fed mice. 

Results We fed mice for 8 and 16 weeks with a WDF diet to induce increasing stages of NAFLD. Both timepoints increased liver TG concentrations significantly. Moreover, at 8 weeks the inflammatory markers TNFα and IL1β mRNA are increased and at 16 weeks these are further increased together with the inflammatory and fibrosis markers αSMA, col1α, TGFβ, TIMP1, and IL6 mRNA. Liver Dio1 was increased during 8 and 16 weeks which was significantly associated with a higher T3/T4 ratio. We further investigated if this increased Dio1 is a compensatory mechanism to reduce steatosis. Dio1 KD mice fed a WDF diet showed increased liver TG and a trend towards increased inflammation compared to control shRNA. In vitro studies indicate reduced beta-oxidation of fatty acids after Dio1 KD.

Conclusion We found that Dio1 is increased during early NAFLD indicating a compensatory mechanism to increase bioactive T3, activate beta-oxidation of fatty acids and reduce the amount of steatosis.