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It has been reported that HT R involves
It has been reported that 5-HT2R involves in type 2 diabetes mellitus and 5-HT-induced IR [22,23]. The present study also demonstrated that it is 5-HT2R rather than other 5-HT receptors, including 5-HT1BR and 5-HT7R, in the liver that mediates HFD-induced abnormality of hepatic lipid metabolism, and it may be both 5-HT2AR and 5-HT2BR instead of 5-HT2AR alone to act. Another novel discovery in the present study was that hepatocytes expressed 5-HT-synthetic enzymes, Tph1 and AADC, both of which were up-regulated by long-term HFD feeding, leading to a high 5-HT level in the liver tissue. This phenomenon was also confirmed in the HepG2 9-AC australia exposed to PA in vitro, and 5-HT inside the hepatocytes could be exported, forming a high 5-HT micro-environment surrounding the cells, which would bind to the 5-HT receptors. Actually, peripheral 5-HT synthesis involves in energy metabolism has been reported: Tph1-deficient mice fed with HFD are protected from obesity, IR and NAFLD, exhibiting greater energy expenditure by brown and white adipose tissue [24]. But, it was not noticed that the high content of 5-HT within liver tissue induced by HFD comes from the liver itself rather than from the blood, although it is generally believed that the majority of 5-HT in periphery is synthesised in the enterochromaffin cell, a type of epithelial cell in gastrointestinal tract [25].
It has been demonstrated that mTOR activation is key for l-tryptophan-mediated exacerbation of hepatic steatosis in the high-calorie diet-fed mice [8], and mTOR activation is also involved in 5-HT-induced IR in the adipocytes and myotubes through inhibiting insulin-stimulated activation of IRS-1-Akt signalling pathway and glucose uptake [26]. In the present study, hepatic mTOR-S6K pathway was activated by both 5-HT and HFD and further activated by a combination of both, and this was also found in HepG2 cells exposed to 5-HT or PA, while Sar treatment abolished it markedly. However, the mTOR activation by 5-HT through acting on 5-HT2R might be just one of the mechanisms for that 5-HT—5-HT2R pathway mediates HFD-induced TG and VLDL overproduction in the hepatocytes, since in HepG2 cells RAP, an mTOR inhibitor fully abolished while Sar partly abolished PA-induced mTOR activation, while Sar's effects on suppressing PA-induced up-regulation of GPAT1 and MTTP, and overproduction of TG and VLDL with lipid droplets were more effective than RAP, indicating that there are other mechanisms for 5-HT by acting on 5-HT2R mediated FA-induced lipid metabolic abnormality in the hepatocytes.
Taken together, our results suggest that the up-regulation of 5-HT2AR and 5-HT2BR with 5-HT synthesis in the liver induced by a long-term HFD feeding play important role in HFD-induced lipid metabolic abnormality in the liver. We speculated that HFD by increasing FFA level in the blood induces up-regulation of 5-HT synthesis and 5-HT2R in the liver, then 5-HT autocrine through 5-HT transporter in the hepatocytes to act on 5-HT2R mediates activation of mTOR-S6K pathway, which leads to HFD-induced hepatic steatosis and VLDL overproduction, hyperlipidemia, and so on. Thus, blocking 5-HT2R with inhibiting 5-HT synthesis in the periphery may be a novel target for treatment of NAFLD and hyperlipidemia.
Authors’ contribution
Funding
Funding for this study was provided by National Natural Science Foundation of China (no. 81570720), the Zhejiang Huahai Pharmaceuticals Co., Ltd. innovation funding for postgraduates of China Pharmaceutical University, (no. CX13S-003HH), and the College Students Innovation Project for the R&D of Novel Drugs (no. SZ14122).
Conflicts of interest
Acknowledgments
M100907 (), also known as volinanserin, is a highly selective 5-HTR receptor antagonist developed initially by Sanofi-Aventis for the treatment of schizophrenia and sleep disorders. Our group reported that M100907 derivatives substituted at the methoxy group of the catechol ring retain the 5-HTR antagonist activity with either the ketone () or racemic hydroxyl group () at the benzylic position., Reported here is the installation of a polyethylene glycol (PEG) linker substituted at the methoxy group of M100907 and the chiral resolution of the molecule to provide a version of M100907 possessing an ether tether that is terminated with an azide () or an alkyne (). The azide on () will be used for future connection to other molecules such as fluorophores, affinity tags and other receptor ligands ().,