Effect of the ligands of thyroid hormone receptor on non-alcoholic fatty liver disease

The term non-alcoholic fatty liver disease (NAFLD) has been used as a general name for conditions ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. End-stage NAFLD cirrhosis carries a substantial risk for early hepatocellular carcinoma development. Therefore, there is an increasing need for new therapeutic approaches for the treatment of this liver disease. Here, we examined the effect of the thyroid hormone triiodothyronine (T3) and the agonist of the thyroid hormone receptor β isoform (TRβ), GC-1, on fatty liver and steatohepatitis induced in rodents by a choline-deficient, methionine-restricted (CMD) diet. Male Fischer rats fed the CMD diet for 1 week developed a marked fatty liver and mild hepatitis. Concurrent administration of T3 resulted in a complete prevention of the fatty change associated with increased mitochondrial and peroxisomal fatty acid beta-oxidation. To investigate whether T3 could also reverse fully established fatty liver, rats were fed the CMD diet for 10 weeks and then cofed T3 for 1 week. Coadministration of T3 resulted in a complete regression of liver steatosis associated with a decrease of lipid peroxidation, cyclooxygenase-2 expression, and activation of phospho-STAT3 and phospho-SAPK/JNK. Finally, additional experiments showed that GC-1, which has no significant side effects on heart rate, prevented and reverted CMD-induced fat accumulation. These results indicate that TR agonists have the potential to inhibit or reverse hepatic steatosis induced by a nutritional model.