Xin Li1, Keke Guo1, Tao Li1, Shaoxin Ma1, Shanshan An1, Shanshan Wang1, Jiao Di2, Siyu He2, Jihua Fu3. 1. Postgraduates of China Pharmaceutical University, Nanjing, China. 2. Undergraduates of China Pharmaceutical University, Nanjing, China. 3. Department of Physiology, China Pharmaceutical University, Nanjing, China. Electronic address: jihua_fu@cpu.edu.cn.
Abstract
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: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. CONCLUSIONS: 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.