title: Serotonin receptor type 3 antagonists improve obesity-associated fatty liver disease in mice.
abstract: 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-HT(3)R) are key factors in the regulation of intestinal motility and permeability. Therefore, we studied the effect of the 5-HT(3)R 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.
authors: Department of Nutritional Medicine (180), University of Hohenheim, Fruwirthstr. 12, 70599 Stuttgart, Germany.
authors: Synia
authors: S
authors: Haub
authors: Yvonne
authors: Y
authors: Ritze
authors: Inga
authors: I
authors: Ladel
authors: Karolin
authors: K
authors: Saum
authors: Astrid
authors: A
authors: Hubert
authors: Astrid
authors: A
authors: Spruss
authors: Christian
authors: C
authors: Trautwein
authors: Stephan C
authors: SC
authors: Bischoff
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D001391:Azo Compounds / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004731:Endotoxins / Q000097:blood; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology; D007546:Isoquinolines / Q000494:pharmacology*; D020738:Leptin / Q000172:deficiency* / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000473:pathology; D000077924:Palonosetron; D011506:Proteins / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology*; D000077526:Tropisetron; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000199:Actins; D001391:Azo Compounds; D004731:Endotoxins; D007211:Indoles; D007546:Isoquinolines; D020738:Leptin; D011506:Proteins; D011812:Quinuclidines; D058831:Serotonin 5-HT3 Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D012701:Serotonin; D000077924:Palonosetron; D000077526:Tropisetron; C011049:oil red O