title: Serotonin protects mouse liver from cholestatic injury by decreasing bile salt pool after bile duct ligation.
abstract: Obstructive cholestasis induces liver injury, postoperative complications, and mortality after surgery. Adaptive control of cholestasis, including bile salt homeostasis, is necessary for recovery and survival. Peripheral serotonin is a cytoprotective neurotransmitter also associated with liver regeneration. The effect of serotonin on cholestatic liver injury is not known. Therefore, we tested whether serotonin affects the severity of cholestatic liver injury. We induced cholestasis by ligation of the bile duct (BDL) in either wild-type (WT) mice or mice lacking peripheral serotonin (Tph1(-/-) and immune thrombocytopenic [ITP] mice). Liver injury was assessed by the levels of plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and tissue necrosis. Bile salt-regulating genes were measured by quantitative polymerase chain reaction and confirmed by western blotting and immunohistochemistry. Tph1(-/-) mice displayed higher levels of plasma AST, ALT, bile salts, and hepatic necrosis after 3 days of BDL than WT mice. Likewise, liver injury was disproportional in ITP mice. Moreover, severe cholestatic complications and mortality after prolonged BDL were increased in Tph1(-/-) mice. Despite the elevation in toxic bile salts, expression of genes involved in bile salt homeostasis and detoxification were not affected in Tph1(-/-) livers. In contrast, the bile salt reabsorption transporters Ostα and Ostβ were up-regulated in the kidneys of Tph1(-/-) mice, along with a decrease in urinary bile salt excretion. Serotonin reloading of Tph1(-/-) mice reversed this phenotype, resulting in a reduction of circulating bile salts and liver injury.
  
  
  CONCLUSIONS
  We propose a physiological function of serotonin is to ameliorate liver injury and stabilize the bile salt pool through adaptation of renal transporters in cholestasis.
authors.affiliation: Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Surgery,University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jae-Hwi
authors.initials: JH
authors.lastname: Jang
authors.forename: Andreas
authors.initials: A
authors.lastname: Rickenbacher
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Dimitri Aristotle
authors.initials: DA
authors.lastname: Raptis
authors.forename: Kuno
authors.initials: K
authors.lastname: Lehmann
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Moritz
authors.forename: Christopher
authors.initials: C
authors.lastname: Soll
authors.forename: Panco
authors.initials: P
authors.lastname: Georgiev
authors.forename: David
authors.initials: D
authors.lastname: Fischer
authors.forename: Endre
authors.initials: E
authors.lastname: Laczko
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001652:Bile Ducts / Q000601:surgery; D002478:Cells, Cultured; D002779:Cholestasis / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008026:Ligation / Q000379:methods; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D012680:Sensitivity and Specificity; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D012701:Serotonin