Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression

Abstract

ObjectiveNon-alcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive non-alcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of the prohormone thyroxine (T4) have a higher incidence of NAFLD and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase 1 (Dio1) is a hepatic enzyme that converts T4 to the bioactive T3, and therefore regulates intracellular thyroid hormone availability in the liver. The role of this intracellular regulation was investigated during the progression of NAFLD. MethodsWe investigated intracellular thyroid hormone metabolism in two NAFLD models: wildtype mice fed Western diet with fructose and Leprdp mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity and metabolic parameters were measured. ResultsDio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T3/T4 ratio. Prevention of this increase by AAV8-mediated liverspecific Dio1 knockdown increased hepatic triglycerides and cholesterol as well as decreased pACC/ACC ratio and acylcarnitine levels suggesting there was lower {beta}-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation. ConclusionHepatic Dio1 gene expression was modulated by dietary conditions, increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms to reduce hepatosteatosis and prevent NASH progression.