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Gastroenterology. 2007 Aug;133(2):608-18. Epub 2007 May 21.

Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis.

Author information

1
Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland.

Abstract

BACKGROUND AND AIMS:

Nonalcoholic steatohepatitis (NASH) is one of the most common causes of liver enzyme elevation in the West. Its prevalence is likely to increase further, paralleling the epidemic increase of the metabolic syndrome. Serotonin degradation by monoamine oxidase A (MAO-A) was recently implicated as an important source of reactive oxygen species. We therefore tested the pathogenetic role of serotonin in a murine model of diet-induced steatohepatitis.

METHODS:

Wild-type and serotonin-deficient mice, tryptophan hydroxylase 1 (Tph1(-/-)) were fed a choline-methionine-deficient diet for 2 and 6 weeks. MAO-A was inhibited with clorgyline. Steatosis, hepatocyte injury, and hepatic inflammation were assessed by histology, immunohistochemistry, and biochemical analysis. Expression levels of MAO-A and serotonin transporter were analyzed by reverse-transcription polymerase chain reaction and Western blot. Oxidative stress was detected by measuring lipid peroxidation. Mitochondrial damage was determined by electron microscopy and quantification of cytochrome c release.

RESULTS:

After choline-methionine-deficient diet, Tph1(-/-) mice displayed an equal degree of steatosis, yet reduced hepatocellular injury and less severe inflammation. The difference in these NASH-defining features could be attributed to an increased uptake and catabolism of serotonin, yielding enhanced levels of reactive oxygen species and lipid peroxides, which mediated hepatocellular injury by mitochondrial damage and inflammation. Inhibition of MAO-A reduced hepatocellular damage in wild-type mice. Correspondingly, MAO-A expression was up-regulated significantly in human NASH.

CONCLUSIONS:

This study provides evidence that serotonin plays a role in the pathogenesis of steatohepatitis, and therefore might represent a novel target for the prevention and treatment of NASH.

PMID:
17681180
DOI:
10.1053/j.gastro.2007.05.019
[Indexed for MEDLINE]

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