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Serotonin protects mouse liver from cholestatic injury by decreasing bile salt pool after bile duct ligation


Jang, Jae-Hwi; Rickenbacher, Andreas; Humar, Bostjan; Weber, Achim; Raptis, Dimitri Aristotle; Lehmann, Kuno; Stieger, Bruno; Moritz, Wolfgang; Soll, Christopher; Georgiev, Panco; Fischer, David; Laczko, Endre; Graf, Rolf; Clavien, Pierre-Alain (2012). Serotonin protects mouse liver from cholestatic injury by decreasing bile salt pool after bile duct ligation. Hepatology, 56(1):209-218.

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. CONCLUSION: 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.

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. CONCLUSION: 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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Functional Genomics Center Zurich
04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Visceral and Transplantation Surgery
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:16 Nov 2012 07:49
Last Modified:07 Dec 2017 16:14
Publisher:Wiley-Blackwell
ISSN:0270-9139
Publisher DOI:https://doi.org/10.1002/hep.25626
PubMed ID:22290718

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