Zhang, JingyaoSong, SidongPang, QingZhang, RuiyaoZhou, LeiLiu, SushunMeng, FandiWu, QifeiLiu, Chang2015-03-022015Zhang, Jingyao, Sidong Song, Qing Pang, Ruiyao Zhang, Lei Zhou, Sushun Liu, Fandi Meng, Qifei Wu, and Chang Liu. 2015. “Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice.” Scientific Reports 5 (1): 8098. doi:10.1038/srep08098. http://dx.doi.org/10.1038/srep08098.2045-2322http://nrs.harvard.edu/urn-3:HUL.InstRepos:14065421Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)).Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH2-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.en-USJournal Article2015-03-0210.1038/srep08098