711 5-LIPOXYGENASE ACTIVATING PROTEIN, FLAP, SIGNALS ADIPOSE TISSUE INFLAMMATION AND STEATOGENIC POTENTIAL IN OBESITY

Background and Aims: Results of human and animal studies have suggested that alterations in intestinal motility, small intestinal bacterial overgrowth and increased intestinal permeability are involved in the development of NAFLD.Serotonin and its receptor 5-HT3R are key factors in the regulation of intestinal motility and recently have also been suggested to be involved in regulating permeability.Therefore, the aim of the present study was to investigate the effect of the intestinal 5-HT3R antagonist tropisetron on the development of steatohepatitis in genetically obese ob/ob mice.Methods: Four week old ob/ob knockout and C57/Bl6 wild-type mice had ad libitum access to plain water or water containing tropisetron for 6 weeks.Markers of liver damage were assessed.In addition mRNA expression of TNFa and MyD88 were determined by real time RT-PCR and endotoxin levels in portal plasma were determined using a LAL test.Serotonin reuptake transporter (SERT) and occludin protein concentrations were determined by Western blot and the number of 5-HT-positive cells was measured by immunhistochemistry in the small intestine.Results: Treatment with tropisetron significantly inhibited the development of NASH in ob/ob mice, leading to a marked decrease in hepatic steatosis and inflammation.In addition, tropisetron treatment blocked hepatic MyD88 and TNFa expression in ob/ob mice down to a level of wild-type controls.In vehicle treated ob/ob mice portal endotoxin levels were significantly increased by ~10-fold in comparison to wildtype controls.In contrast, in tropisetron treated mice, endotoxin levels in portal plasma were even lower than in wild-type controls.Moreover, concentration of the tight junction protein occludin and of SERT in the duodenum of tropisetron treated ob/ob mice was markedly increased in comparison to all other groups.However, the number of 5-HT-positive cells in the duodenum was not affected by tropisetron treatment.Conclusion: Our data suggests that alterations in the intestinal serotonergic system and herein practically the 5-HT3R may be involved in the regulation of intestinal permeability and subsequently the development of NASH in obese ob/ob mice and that the 5-HT3R might be a new target for the therapy against NASH.