PT - JOURNAL ARTICLE AU - Synia Haub AU - Yvonne Ritze AU - Inga Ladel AU - Karolin Saum AU - Astrid Hubert AU - Astrid Spruss AU - Christian Trautwein AU - Stephan C. Bischoff TI - Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice AID - 10.1124/jpet.111.181834 DP - 2011 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 790--798 VI - 339 IP - 3 4099 - http://jpet.aspetjournals.org/content/339/3/790.short 4100 - http://jpet.aspetjournals.org/content/339/3/790.full SO - J Pharmacol Exp Ther2011 Dec 01; 339 AB - Obesity is a major cause for nonalcoholic fatty liver disease (NAFLD). Previous studies suggested that alterations in intestinal motility and permeability contribute to the development of NAFLD. Serotonin and serotonin receptor type 3 (5-HT3R) are key factors in the regulation of intestinal motility and permeability. Therefore, we studied the effect of the 5-HT3R antagonists tropisetron and palonosetron on the development of NAFLD in leptin-deficient obese mice. Four-week-old ob/ob mice and lean controls were treated for 6 weeks orally with tropisetron or palonosetron at 0.2 mg/kg per day. We determined markers of liver damage and inflammation, portal endotoxin levels, and duodenal concentrations of serotonin, serotonin-reuptake transporter (SERT), occludin, and claudin-1. Tropisetron treatment significantly reduced liver fat content (−29%), liver inflammation (−56%), and liver cell necrosis (−59%) in ob/ob mice. The beneficial effects of tropisetron were accompanied by a decrease in plasma alanine aminotransferase and portal vein plasma endotoxin levels, an attenuation of enhanced MyD88 and tumor necrosis factor-α mRNA expression in the liver, and an increase of tight junction proteins in the duodenum. Tropisetron treatment also caused a reduction of elevated serotonin levels and an increase of SERT in the duodenum of ob/ob mice. Palonosetron had similar effects as tropisetron with regard to the reduction of liver fat and other parameters. Tropisetron and palonosetron are effective in attenuating NAFLD in a genetic mouse model of obesity. The effect involves the intestinal nervous system, resulting in a reduction of endotoxin influx into the liver and subsequently of liver inflammation and fat accumulation.