Non-alcoholic Fatty Liver Disease (NAFLD) promotes to Non-alcoholic Steatosis Hepatitis (NASH), liver cirrhosis and cancer. However, there is no specific clinical treatment for NASH. Previously, we screened in vitro model for novel drug candidates towards NAFLD/NASH. The mTOR inhibitor was found to significantly alleviate palmitic acid-induced lipotoxicity in hepatocyte culture. Therefore, the aim of presented study was to investigate the effect of non-specific mTOR inhibitor (KU-0063794) when given orally in dietary model of NAFLD/NASH. To develop NAFLD and NASH in vivo, male mice C57Bl6J were fed with Atherogenic High Fat Diet (AHFD), and fructose/glucose in drinking water for 12 and 16 weeks, respectively. KU-0063794 treatment for 17 days displayed a trend towards decreasing serum glucose, inflammation (e.g. serum TNF-α), hepatocyte oxidative stress (e.g. conjugated DENES) and an improvement in expression of metabolic genes in liver homogenates. However, KU-0063794 had no effect on liver NASH morphology (e.g. NAS or fibrosis score). In conclusion, oral KU-0063794 treatment for an acute period displayed a trend to improve the highly progressed NASH with no signs of toxicity and therefore, chronic treatment should follow.

Keywords: Atherogenic high fat diet; NAFLD/NASH; lipotoxicity; oxidative stress; mTOR inhibitor