Abstract
The precipitous increase in occurrence of non-alcoholic steatohepatitis (NASH) is a serious threat to public health worldwide. The pathogenesis of NASH has not yet been thoroughly studied. We aimed to elucidate the interplay between serotonin (5-hydroxytryptamine, 5-HT) and NASH. The serum 5-HT levels in patients with non-alcoholic fatty liver disease (NAFLD) and a rat fed with high fat-sucrose diet (HFSD) were evaluated using liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF MS)/MS. The peripheral Tph1 inhibitor, LP533401, and a tryptophan (TRP)-free diet were administered to rats with NASH, induced by HFSD. BRL-3A cells were treated with 1 mM free fatty acids (FFAs) and/or 50 μM 5-HT, and then small interfering RNA (siRNA) targeting the 5-HT2A receptor (HTR2A) and the PPARγ pharmaceutical agonist, pioglitazone, were applied. We found a marked correlation between 5-HT and NASH. The absence of 5-HT, through the pharmaceutical blockade of Tph1 (LP533401) and dietary control (TRP-free diet), suppressed hepatic lipid load and the expression of inflammatory factors (Tnfα, Il6, and Mcp-1). In BRL-3A cells, 50 μM 5-HT induced lipid accumulation and upregulated the expression of lipogenesis-ralated genes (Fas, Cd36, and Plin2) and the inflammatory response. Specifically, HTR2A knockdown and evaluation of PPARγ agonist activity revealed that HTR2A promoted hepatic steatosis and inflammation by activating PPARγ2. These results suggested that duodenal 5-HT was a risk factor in the pathological progression of NASH. Correspondingly, it may represent an attractive therapeutic target for preventing the development of NASH via the regulation of the HTR2A/PPARγ2 signaling pathway.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is emerging as a chronic liver disease worldwide, especially in affluent areas within Western countries
Increased Gut-Derived Serotonin Signaling in the Duodenum Was Correlated With Non-Alcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis
We speculated that serum 5-HT may have been associated with nonalcoholic fatty liver disease (NAFLD)
Summary
Non-alcoholic fatty liver disease (NAFLD) is emerging as a chronic liver disease worldwide, especially in affluent areas within Western countries. It is characterized by the extensive accumulation of fats in the liver, and always associated with obesity, insulin resistance (IR), type 2 diabetes mellitus, druginduced liver injury, and other metabolic syndrome diseases (Kawano and Cohen, 2013; Willebrords et al, 2015). 10–20% of patients with NAFLD experience non-alcoholic steatohepatitis (NASH), which may give rise to cirrhosis, hepatic fibrosis, and eventually hepatocellular carcinoma; some liver-related mortality occurs (Loomba and Sanyal, 2013; Singh et al, 2015). The increase in liver- and non-liver related morbidity and mortality has been extensively reported in the world (Brodosi et al, 2017). There has been no ratification of pharmacological drugs with clear therapeutic mechanisms for NASH that are able to meet the clinical demands, various nutraceuticals and phytochemicals has been tested
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
