5-HT 2 receptor mediates high-fat diet-induced hepatic steatosis and very low density lipoprotein overproduction in rats

• Published in: Obesity research & clinical practice Vol. 12; no. 1; pp. 16 - 28
• Main Authors: Li, Xin, Guo, Keke, Li, Tao, Ma, Shaoxin, An, Shanshan, Wang, Shanshan, Di, Jiao, He, Siyu, Fu, Jihua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.01.2018
• Subjects: 5-HT 2 receptor; 5-HT synthesis; Animals; Cholesterol, VLDL - biosynthesis; Cholesterol, VLDL - blood; Diet, High-Fat; Disease Models, Animal; Endocrinology & Metabolism; Fatty Liver - blood; Fatty Liver - metabolism; Hepatic lipid abnormality; Internal Medicine; Lipoproteins, VLDL - biosynthesis; Lipoproteins, VLDL - blood; Liver - metabolism; Male; Mammalian target of rapamycin; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT2 - metabolism; Up-Regulation; Hepatic lipid abnormality; 5-HT 2 receptor; Mammalian target of rapamycin; 5-HT synthesis
• ISSN: 1871-403X; 1878-0318
• DOI: 10.1016/j.orcp.2016.03.015

5-HT has been shown to mediate abnormality of hepatic lipid metabolism through activation of mammalian target of rapamycin (mTOR). However, it is unclear whether 5-HT is directly involved in high-fat diet (HFD)-induced hepatic steatosis. Male rats were allocated into seven groups with control, either HFD feeding, 5-HT treatment, or HFD feeding and 5-HT treatment with or without sarpogrelate treatment, all of which were executed for 4 weeks. HepG2 cells were exposed to 5-HT or palmitic acid (PA) with or without rapamycin or Sar treatment. Rats fed with HFD or exposed to 5-HT led to abnormalities with activated hepatic mTOR-S6K pathway, overproduction of hepatic triglycerides and VLDL with steatosis, and hyperlipidemia, which were exacerbated by a combination of HFD and 5-HT. Sarpogrelate significantly inhibited above abnormalities induced by HFD and 5-HT, alone or in a combination. Additionally, HFD caused up-regulation of 5-HT2 receptors (5-HT2R), including 5-HT2AR and 5-HT2BR, and 5-HT synthesis in the liver, without obvious influence on other 5-HT receptors gene expression. In HepG2 cells, both PA and 5-HT induced overproduction of triglycerides and VLDL with lipid droplets, and PA up-regulated 5-HT2AR and 5-HT2BR expression and 5-HT synthesis as well. Rapamycin fully abolished PA or 5-HT-induced mTOR activation, which was more effective than sarpogrelate. However, the inhibitory effects of rapamycin on PA or 5-HT-induced overproduction of triglycerides and VLDL were less than sarpogrelate. Up-regulation of hepatic 5-HT2R and 5-HT synthesis by HFD is crucial for HFD-induced overproduction of hepatic triglycerides and VLDL with hyperlipidemia.