Metabolomics-based search for therapeutic agents for non-alcoholic steatohepatitis

• We subjected liver of MCD diet-induced steatohepatitis model to metabolome analysis.
• Hypotaurine exhibited the greatest decrease in hepatic concentration in the model.
• Hypotaurine attenuated liver damage of MCD diet-induced steatohepatitis.
• Hypotaurine exhaustion was also confirmed in the obese model using ob/ob mice.
• Hypotaurine supplementation improved insulin sensitivity in ob/ob mice.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the commonest form of chronic liver disease in developed countries. Non-alcoholic steatohepatitis (NASH), which represents advanced stage NAFLD, is increasingly being recognized as a major cause of liver-related morbidity and mortality. However, no effective drugs against NASH have yet been developed. Therefore, we searched for candidate therapeutic agents based on the changes in levels of hepatic metabolites via gas chromatography mass spectrometry (GC/MS)-based metabolome analysis of livers from methionine-choline deficient (MCD) diet-fed mice, a mouse model of NASH.MethodsThe metabolites were extracted from the livers of the MCD diet-fed mice and then analyzed using GC/MS. Subsequently, the MCD diet-fed mice were supplemented with hypotaurine, and the therapeutic effects of hypotaurine against steatohepatitis were evaluated.ResultsNinety-nine metabolites were detected in the livers of the MCD diet-induced steatohepatitis model mice. Among these metabolites, hypotaurine exhibited the greatest decrease in its concentration in the mice. Supplementation with 2 mmol/kg BW hypotaurine attenuated liver injuries and fat accumulation caused by the MCD diet-induced steatohepatitis. Furthermore, 10 mmol/kg BW hypotaurine supplementation ameliorated fibrosis and oxidative stress induced by the MCD diet.ConclusionThe present metabolome analysis-based study demonstrated that hypotaurine is a novel candidate therapeutic agent for NASH.