Z Gastroenterol 2009; 47 - P2_08
DOI: 10.1055/s-0029-1191819

Rapamycin decreases proinflammatory and profibrogenic gene expression in experimental NASH

E Gäbele 1, K Dostert 1, C Dorn 1, G Koehl 2, EK Geissler 2, J Schoelmerich 1, C Hellerbrand 1
  • 1Klinik und Poliklinik für Innere Medizin I, Universitätsklinikum Regensburg
  • 2Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg

Aims: Because of the increasing incidence of NASH and obesity in the western world, the use of fatty grafts for patients requiring liver transplantation is an evolving problem. Rapamycin, which has antifibrotic properties, is an immunosuppressant widely used after liver transplantation. Therefore, we hypothesized that rapamycin could attenuate profibrogenic and proinflammatory gene expression in a model of dietary NASH.

Methods: Female Balb/c mice (n=4–6) were allocated into four experimental groups receiving standard chow (SC) or a high fat (HF) diet with or without rapamycin supplementation (5mg/kg bodyweight) for 3 and 6 weeks. The high fat diet was prepared by adding fat (50% lard and 50% cocoa butter), cholesterol and cholate to the standard chow diet resulting in a dietary composition of 17% fat, 1,25% cholesterol and 0,5% cholate. In rapamycin treated mice, serum concentrations of rapamycin were monitored every other week. After the experimental period serum and liver tissue were obtained for further analysis.

Results: Rapamycin serum levels were 14±2 ng/ml. HF diet increased liver to body weight ratios from 4.5% in control animals to about 9% in both HF groups. Liver injury, indicated by ALT serum levels, significantly increased in HF fed animals (401±127 U/l compared to 27±34 U/l); however, rapamycin treatment clearly decreased HF-induced ALT values (310±59 U/l). Similar results were found for AST values. Following HF diet, hepatic expression of TNF-, IL1-, TIMP1- and collagen I-mRNA levels was increased compared to mice fed SC diet. Rapamycin treatment significantly blunted HF-induced elevation of IL1-, TIMP1- and collagen I-mRNA levels.

Conclusion: Rapamycin prevents proinflammatory and profibrogenic gene expression in a new model of experimental NASH. Rapamycin might therefore be a promising anti-inflammatory and anti-fibrotic long-term therapy for patients receiving fatty grafts after liver transplantation.

NASH - Rapamycin - fibrosis - immunosuppression - inflammation