Gut-Derived Serotonin Contributes to the Progression of Non-Alcoholic Steatohepatitis via the Liver HTR2A/PPARγ2 Pathway

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 (5hydroxytryptamine, 5-HT) and NASH. The serum 5-HT levels in patients with nonalcoholic 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 mM 5-HT, and then small interfering RNA (siRNA) targeting the 5-HT2A receptor (HTR2A) and the PPARg 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 (Tnfa, Il6, and Mcp-1). In BRL-3A cells, 50 mM 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 PPARg agonist activity revealed that HTR2A promoted hepatic steatosis and inflammation by activating PPARg2. 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/PPARg2 signaling pathway.

The Identification of the Biomarkers of Sheng-Ji Hua-Yu Formula Treated Diabetic Wound Healing Using Modular Pharmacology

“…The results on mRNA expression of Htr2a reflected those in the previous study of Yang et al, who had also found that accumulation of macrophages and neutrophils along with increased levels of inflammatory cytokines, were associated with inflammation ( Yang et al, 2020 ). Meanwhile, the absence of 5-HT suppressed hepatic lipid load and the expression of inflammatory factors, including TNF-α, IL-6, and MCP1 ( Wang L. et al, 2020 ). Another animal experiment also validated that HTR2A was upregulated significantly after inflammation/pain in the dorsal root ganglion following disc puncture in rats ( Fujioka et al, 2016 ).…”

Intestinal Dysbiosis, the Tryptophan Pathway and Nonalcoholic Steatohepatitis

“…In a high-fat high-sucrose diet rat model, inhibition of TPH1 by LP533401 or dietary control of tryptophan reduced hepatic steatosis and expression of inflammatory factors Tnfa , Il-6 , and Mcp-1 genes. 55 In BRL-3A cells, 5-HT increased expression of lipogenesis-related genes Fas , Cd36 , and Plin2 . Wang et al 55 also demonstrated that 5-HT bound to its receptor HTR2A activated PPAR-gamma2, progressing lipid accumulation and proinflammatory factor production.…”

“…It has been demonstrated that 5-HT is increased in NASH both in patients and animal models. Wang et al 55 characterized blood levels of 5-HT in NASH patients and found that it was highly increased. Choi et al 56 showed that the hepatic steatosis induced by a high-fat diet was dependent on increased blood concentrations of 5-HT.…”

Role of microbiota and related metabolites in gastrointestinal tract barrier function in NAFLD

“… 207 Interestingly, evidence of a correlation between 5HT and NASH has been recently shown in serum levels of NAFLD patients and in serum levels and duodenum of rat fed with high fat-sucrose diet inducing NASH. 211 The inhibition of 5HT in those rats and in in vitro models of NAFLD alleviates hepatic lipid accumulation and inflammation. 211 The detrimental role of 5HT in NAFLD has also been shown in Tph1 knockout mice.…”

“… 211 The inhibition of 5HT in those rats and in in vitro models of NAFLD alleviates hepatic lipid accumulation and inflammation. 211 The detrimental role of 5HT in NAFLD has also been shown in Tph1 knockout mice. 212 , 213 where 5HT is able to upregulate lipogenic genes in the liver through hepatic serotonin receptor HTR2A.…”