Rapamycin aggravates experimental non alcoholic steatohepatitis in mice

Aims: The increasing incidence of the metabolic syndrome not only contributes to a larger number of obese patients developing non-alcoholic steatohepatitis (NASH) after liver transplantation (LTx), but also led to a rising number of fatty grafts used for LTx. Rapamycin is a common immunosuppressant after organ transplantation. Notably, the mTOR inhibitor rapamycin has potent antifibrotic properties and affects lipid accumulation. Therefore, we hypothesized whether rapamycin would attenuate hepatic steatosis, inflammation and fibrogenesis in an experimental model of NASH. Methods: Mice were allocated into four experimental groups receiving ether standard chow (SC) or a high fat (HF) diet with or without rapamycin supplementation in immunosuppressive doses (6mg/kg bodyweight) for 6 weeks. Results: Liver to bodyweight ratios and serum levels of transaminases were significantly increased in the HF group, and noteworthy, rapamycin treatment further aggravated these parameters. Moderate histological steatosis was found in HF mice, and it was more pronounced in the rapamycin group. Accordingly, hepatic triglycerides were significantly higher in the HF rapamycin group compared to mice fed HF diet only. Further, HF-diet induced pro-inflammatory (TNF, MCP-1) and pro-fibrogenic (TGF-beta, TIMP-1, Pai-1) gene expression, which was significantly increased by rapamycin, leading to higher induction of collagen I mRNA and protein expression, and more pronounced histological fibrosis. Conclusion: Experimental NASH is aggravated by Rapamycin, which points towards caution with regards to its application in obese patients or patients with fatty liver, respectively.

NASH - Rapamycin - liver fibrosis - mTOR