title: Long-term Stress with Hyperglucocorticoidemia-induced Hepatic Steatosis with VLDL Overproduction Is Dependent on both 5-HT2 Receptor and 5-HT Synthesis in Liver.
abstract: Hepatic triglycerides production and adipose lipolysis are pivotal for long-term stress (LTS) or hyperglucocorticoidemia-induced insulin resistance. 5-hydroxytryptamine (5-HT) has been demonstrated to induce hepatic lipid metabolic abnormality by activating mammalian target of rapamycin (mTOR). In present study, we explored whether 5-HT is involved in LTS effects in liver using restraint stress-exposed rats and cultured primary rat hepatocytes and HepG2 cells. LTS with hyperglucocorticoidemia induced hepatic 5-HT synthetic increase with tryptophan hydroxylase 1 (Tph1) up-regulation, and 5-HT2 receptor (5-HT2R, including 5-HT2A, 2B receptor) up-regulation in liver and visceral adipose, as well as hepatic mTOR activation with triglycerides and VLDL overproduction with steatosis, and visceral adipose lipolytic increase with high blood free fatty acids (FFAs) level. 5-HT exposure exhibited LTS-like effects in both tissues, and both LTS and 5-HT effects could be abolished significantly by blocking 5-HT2R. In HepG2 cells dexamethasone or palmitate-induced mTOR activation with triglycerides and VLDL overproduction were accompanied by up-regulations of 5-HT synthesis and 5-HT2R, which were significantly abolished by gene silencing Tph1 or 5-HT2R and were almost fully abolished by co-silencing of both, especially on VLDL overproduction. Chemical inhibition of Tph1 or/and 5-HT2R in both hepatocytes exhibited similar abolishment with genetic inhibition on dexamethason-induced effects. 5-HT-stimulated effects in both hepatocytes were fully abolished by blocking 5-HT2R, while 5-HT itself also up-regulated 5-HT2R. In conclusion, up-regulated hepatic 5-HT synthesis and 5-HT2R induced by both glucocorticoid and FFAs are crucial for LTS-induced hepatic steatosis with VLDL overproduction, while 5-HT by acting on 5-HT2R mediates mTOR activation in liver.
authors.affiliation: 1. Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Jihua
authors.initials: J
authors.lastname: Fu
authors.affiliation: 1. Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Shaoxin
authors.initials: S
authors.lastname: Ma
authors.affiliation: 1. Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: 1. Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: An
authors.affiliation: 1. Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: 1. Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Keke
authors.initials: K
authors.lastname: Guo
authors.affiliation: 1. Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Lin
authors.affiliation: 1. Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qu
authors.affiliation: 1. Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wang
authors.affiliation: 2. Undergraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Xinyue
authors.initials: X
authors.lastname: Dong
authors.affiliation: 2. Undergraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Han
authors.affiliation: 2. Undergraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Fu
authors.affiliation: 2. Undergraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Xinping
authors.initials: X
authors.lastname: Huang
authors.affiliation: 2. Undergraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Tianying
authors.initials: T
authors.lastname: Wang
authors.affiliation: 2. Undergraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Siyu
authors.initials: S
authors.lastname: He
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015243:Cholesterol, VLDL / Q000096:biosynthesis*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000378:metabolism; D020868:Gene Silencing; D005938:Glucocorticoids / Q000097:blood; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D017207:Rats, Sprague-Dawley; D044348:Receptors, Serotonin, 5-HT2 / Q000096:biosynthesis* / Q000235:genetics; D012701:Serotonin / Q000096:biosynthesis*; D015398:Signal Transduction; D013312:Stress, Physiological; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015243:Cholesterol, VLDL; D005230:Fatty Acids, Nonesterified; D005938:Glucocorticoids; D044348:Receptors, Serotonin, 5-HT2; D012701:Serotonin; D014365:Tryptophan Hydroxylase
keywords: 5-hydroxytryptamine 2A, 2B receptor (5-HT2A, 2BRs); 5-hydroxytryptamine synthesis; Long-term stress; Triglycerides (TGs) synthesis; Very low-density lipoprotein (VLDL) assembly