Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice.
Elevated dietary fructose intake, altered intestinal motility, and barrier function may be involved in the development of nonalcoholic fatty liver disease (NAFLD). Because intestinal motility and permeability are also regulated through the bioavailability of serotonin (5-HT), we assessed markers of hepatic injury in serotonin reuptake transporter knockout (SERT(-/-)) and wild-type mice chronically exposed to different monosaccharide solutions (30% glucose or fructose solution) or water for 8 wk. The significant increase in hepatic triglyceride, TNF-alpha, and 4-hydroxynonenal adduct as well as portal endotoxin levels found in fructose-fed mice was associated with a significant decrease of SERT and the tight-junction occludin in the duodenum. Similar effects were not found in mice fed glucose. In contrast, in SERT(-/-) mice fed glucose, portal endotoxin levels, concentration of occludin, and indices of hepatic damage were similar to those found in wild-type and SERT(-/-) mice fed fructose. In fructose-fed mice treated with a 5-HT3 receptor antagonist, hepatic steatosis was significantly attenuated. Our data suggest that a loss of intestinal SERT is a critical factor in fructose-induced impairment of intestinal barrier function and subsequently the development of steatosis.
Haub
Synia
S
Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
Kanuri
Giridhar
G
Volynets
Valentina
V
Brune
Thomas
T
Bischoff
Stephan C
SC
Bergheim
Ina
I
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D018938:Caco-2 Cells; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D004731:Endotoxins / Q000097:blood / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D005632:Fructose / Q000008:administration & dosage / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009504:Neutrophils / Q000473:pathology; D062793:Occludin; D009929:Organ Size / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D000077526:Tropisetron; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000447:Aldehydes; D004731:Endotoxins; D007211:Indoles; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D005632:Fructose; D012701:Serotonin; D000077526:Tropisetron; D005947:Glucose; C027576:4-hydroxy-2-nonenal