BACKGROUND
Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, lobular inflammation, and fibrosis. Thyroid hormone (TH) reduces hepatosteatosis; however, the therapeutic effect of TH on NASH associated inflammation and fibrosis, is not known. This study examined the therapeutic effect of TH on hepatic inflammation and fibrosis during NASH, and investigated TH's molecular actions on autophagy and mitochondrial biogenesis.
METHODS
HepG2-TRβ cells were treated with BSA-conjugated palmitic acid (PA) to mimic lipotoxic conditions in vitro. Mice with NASH were established by feeding C57BL/6J mice Western diet with 15% fructose in drinking water for 16 weeks. These mice were administered T3/T4 supplemented in drinking water for the next 8 weeks.
RESULTS
In cultured HepG2-TRβ cells, TH treatment increased mitochondrial respiration and fatty acid oxidation under basal and PA-treated conditions, as well as decreased LPS and PA-stimulated inflammatory and fibrotic responses. In a dietary mouse model of NASH, TH administration decreased hepatic triglyceride content (3.19 ± 0.68 vs. 8.04 ± 0.42 mM/g liver), and hydroxyproline (1.44 ± 0.07 vs. 2.58 ± 0.30 mg/g liver) when compared to mice with untreated NASH. Metabolomics profiling of lipid metabolites showed that mice with NASH had increased triacylglycerol (TAG), diacylglycerol (DAG), monoacylglycerol (MAG), and hepatic cholesterol esters (CE) species, and these lipid species that were decreased by TH treatment. Mice with NASH also showed decreased autophagic degradation as evidenced by decreased TFEB and lysosomal protease expression, and accumulation of LC3B-II and p62. TH treatment restored the level of lysosomal proteins and resolved the accumulation of LC3B-II and p62. Impaired mitochondrial biogenesis also was restored by TH. The simultaneous restoration of autophagy and mitochondrial biogenesis by TH increased β-oxidation of fatty acids. Additionally, the elevated oxidative stress and inflammasome activation in NASH liver also were decreased by TH.
CONCLUSION
In a mouse model of NASH, TH restored autophagy and mitochondrial biogenesis to increase β-oxidation of fatty acids, and reduce lipotoxicity, oxidative stress, hepatic inflammation, and fibrosis. Activating TR in the liver may represent an effective strategy for NASH treatment.