Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis.
OBJECTIVE
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.
Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland.
Antonio
A
Nocito
Felix
F
Dahm
Wolfram
W
Jochum
Jae Hwi
JH
Jang
Panco
P
Georgiev
Michael
M
Bader
Eberhard Ludwig
EL
Renner
Pierre-Alain
PA
Clavien
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002796:Choline Deficiency / Q000150:complications; D003010:Clorgyline / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006505:Hepatitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D014365:Tryptophan Hydroxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D008996:Monoamine Oxidase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D008715:Methionine; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D008995:Monoamine Oxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003010:Clorgyline