Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway.
BACKGROUND
Besides its neurotransmitter and vasoconstriction functions, serotonin is an important mediator of numerous biological processes in peripheral tissues including cell proliferation, steatosis, and fibrogenesis. Recent reports indicate that serotonin may promote tumor growth in liver cancer, however, the molecular mechanisms remain elusive. n this study, we investigated the role and molecular signaling mechanisms mediated by serotonin in liver cancer cell survival, drug resistance, and steatosis.


METHODS
Effect of serotonin on modulation of cell survival/proliferation was determined by MTT/WST1 assay. Effect of serotonin on the regulation of autophagy biomarkers and lipid/fatty acid proteins expression, AKT/mTOR and Notch signaling was evaluated by immunoblotting. The role of serotonin in normal human hepatocytes and liver cancer cell steatosis was analyzed by Oil Red O staining. The mRNA expression levels of lipid/fatty acid proteins and serotonin receptors were validated by qRT-PCR. The important roles of autophagy, Notch signaling, serotonin receptors and serotonin re-uptake proteins on serotonin-mediated cell steatosis were investigated by using selective inhibitors or antagonists. The association of peripheral serotonin, autophagy, and hepatic steatosis was also investigated using chronic EtOH fed mouse model.


RESULTS
Exposure of liver cancer cells to serotonin induced Notch signaling and autophagy, independent of AKT/mTOR pathway. Also, serotonin enhanced cancer cell proliferation/survival and drug resistance. Furthermore, serotonin treatment up-regulated the expression of lipogenic proteins and increased steatosis in liver cancer cells. Inhibition of autophagy or Notch signaling reduced serotonin-mediated cell steatosis. Treatment with serotonin receptor antagonists 5-HTr1B and 5-HTr2B reduced serotonin-mediated cell steatosis; in contrast, treatment with selective serotonin reuptake inhibitors (SSRIs) increased steatosis. In addition, mice fed with chronic EtOH resulted in increased serum serotonin levels which were associated with the induction of hepatic steatosis and autophagy.


CONCLUSIONS
Serotonin regulates liver cancer cell steatosis, cells survival, and may promote liver carcinogenesis by activation of Notch signaling and autophagy.
['Niture|Suryakant|S|', 'Gyamfi|Maxwell A|MA|', 'Kedir|Habib|H|', 'Arthur|Elena|E|', 'Ressom|Habtom|H|', 'Deep|Gagan|G|', 'Kumar|Deepak|D|']
D000818:Animals D001343:Autophagy D049109:Cell Proliferation D002470:Cell Survival D056945:Hep G2 Cells D006801:Humans D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D065626:Non-alcoholic Fatty Liver Disease D051057:Proto-Oncogene Proteins c-akt D044302:Receptor, Serotonin, 5-HT1B D051880:Receptors, Notch D012701:Serotonin D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases
Serotonin Autophagy Notch signaling Drug resistance Cell steatosis