Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway

Abstract

BackgroundBesides 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.MethodsEffect 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.ResultsExposure 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.ConclusionsSerotonin regulates liver cancer cell steatosis, cells survival, and may promote liver carcinogenesis by activation of Notch signaling and autophagy.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0282-6) contains supplementary material, which is available to authorized users.

The Role of the Gut Microbiota in Lipid and Lipoprotein Metabolism

“…This is consistent with emerging studies proposing a role for gut-derived serotonin in obesity [146][147][148]. Interestingly, gut-derived serotonin has been shown to positively regulate liver lipid metabolism [149][150][151]. Using tryptophan hydroxylase 1 knockout mice which lack the enzyme for synthesizing serotonin in the gut, Choi et al found that these mice are protected from HFD-induced fatty liver [149].…”

TNFAIP8 regulates autophagy, cell steatosis, and promotes hepatocellular carcinoma cell proliferation

“…Oil Red O staining-based steatosis quantification HCC cells (1 × 10 4 /well) were grown in 96-well plates in triplicates, transfected with EV or TNFAIP8-Myc plasmids for 24 h, and treated with 100 µM oleic acid for 24 h. After Oil Red O staining, cells were lysed in 100 µl of 1X cell lysis buffer solution (Cell Signaling, Danvers, MA) for 15 min. After gentle shaking, Oil Red O stain released from steatotic cells was transferred to another 96-well plate, and the absorbance at 405 nm was measured using Fluostar Omega plate reader (BMG Lab Tech, Cary, NC) as described previously 19,20 . Experiments were repeated two to three times.…”

Deregulated Serotonin Pathway in Women with Morbid Obesity and NAFLD

“…Additionally, high levels of 5-HT modulate glucose metabolism, enhancing pancreatic insulin secretion, which gives rise to insulin resistance that promotes hepatic steatosis [ 27 , 28 ]. Recently, an in vitro and in vivo study has demonstrated that 5-HT regulates hepatocarcinoma steatosis and may enhance hepatic carcinogenesis [ 29 ]. Furthermore, the inhibition of hepatic serotonin receptor 2A (HTR2A) signaling in vivo by blocking the synthesis of 5-HT improves liver steatosis [ 28 ], as well as hyperglycemia and dyslipidemia [ 30 ].…”