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Int J Biol Sci 2016; 12(2):219-234. doi:10.7150/ijbs.13062

Research Paper

Long-term Stress with Hyperglucocorticoidemia-induced Hepatic Steatosis with VLDL Overproduction Is Dependent on both 5-HT2 Receptor and 5-HT Synthesis in Liver

Jihua Fu, Shaoxin Ma1#, Xin Li1#, Shanshan An1#, Tao Li1#, Keke Guo1#, Min Lin1, Wei Qu1, Shanshan Wang1, Xinyue Dong2, Xiaoyu Han2, Ting Fu2, Xinping Huang2, Tianying Wang2, Siyu He2

1. Postgraduates of China Pharmaceutical University, Nanjing, China
2. Undergraduates of China Pharmaceutical University, Nanjing, China
# These authors contributed equally to this work

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.

Keywords: Long-term stress, 5-hydroxytryptamine 2A, 2B receptor (5-HT2A, 2BRs), 5-hydroxytryptamine synthesis, Triglycerides (TGs) synthesis, Very low-density lipoprotein (VLDL) assembly

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How to cite this article:
Fu J, Ma S, Li X, An S, Li T, Guo K, Lin M, Qu W, Wang S, Dong X, Han X, Fu T, Huang X, Wang T, He S. Long-term Stress with Hyperglucocorticoidemia-induced Hepatic Steatosis with VLDL Overproduction Is Dependent on both 5-HT2 Receptor and 5-HT Synthesis in Liver. Int J Biol Sci 2016; 12(2):219-234. doi:10.7150/ijbs.13062. Available from http://www.ijbs.com/v12p0219.htm