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

doi:10.1016/j.orcp.2016.03.015

Obesity Research & Clinical Practice

Volume 12, Issue 1, Supplement 1, January–February 2018, Pages 16-28

https://doi.org/10.1016/j.orcp.2016.03.015 Get rights and content

Summary

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-HT_2AR and 5-HT_2BR, 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-HT_2AR and 5-HT_2BR 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.

Introduction

5-HT, a monoaminergic neurotransmitter, is synthesised from l-tryptophan catalysed by the enzymes tryptophan hydroxylase (Tph) and aromatic amino acid decarboxylase (AADC) [1]. 5-HT mediates multiple regulations of physiological functions in vivo: in the centre, 5-HT mediates nervous activities related with mood, anxiety, sleep, appetite, and so on [2], [3]; in the periphery, 5-HT involves in regulations of blood pressure, liver repair and fibrosis, gastrointestinal motor activity, haemostatic system, inflammation, and immune responses [4], [5], [6]. Particularly, 5-HT has been demonstrated to control lipid metabolism in the liver. Nocito A et al. [7] has found that Tph1 (a subtype of Tph in periphery)-deficient mice are protected from hepatocellular injury and steatosis on non-alcoholic steatohepatitis (NASH) induced by choline-methionine-deficient diet. And, Yosuke Osawa et al. found that l-tryptophan feeding-caused exacerbation on hepatic steatosis induced by a high fat and high fructose diet owes to 5-HT through the activation of mTOR-p70 S6 kinase (p70S6K) signalling pathway [8]. In the healthy subjects, the serum level of 5-HT is approximately 146 μg/L [9], while in the diabetic patients it would elevate up to 3-fold of normal people [10], [11], suggesting that there is a potential association between dysfunction of energy metabolism and 5-HT. Our previous study suggested that increased 5-HT synthesis induced by glucocorticoid in the liver and intra-abdominal adipose is significantly involved in glucocorticoid-induced insulin resistance (IR) [12].

5-HT plays its role through binding to its receptors (5-HTR). 14 types of 5-HT receptors, subtyped into seven families (named 5-HT1 to 5-HT7 receptor subfamily), are characterised as different signal transduction and physiological roles [13], [14]. 5-HT_{1, 3, 4, 5, 6, 7}Rs mainly distribute in brain regions [15], while 5-HT₂R family includes three subtypes, namely 5-HT2A, 2B, and 2C receptors, all of which are expressed predominantly in the peripheral tissues, such as stomach, intestine, heart, kidney, liver, and adipose tissue [16]. Both 5-HT_2AR and 5-HT_2BR, as well as other 5-HT receptors, are expressed in the liver. However, which 5-HT receptors mediate 5-HT-induced abnormality of hepatic lipid metabolism remains to be elucidated further. In this study, we found that as glucocorticoid-induced IR, 5-HT also involves in HFD-induced hepatic triglycerides (TG) and very-low density lipoprotein (VLDL) overproduction with steatosis in rats, resulting in dyslipidemia, which is mediated by 5-HT₂R.

Section snippets

Animal experiment

Male Sprague-Dawley rats (8-week old), supplied by B&K Universal Group Limited (Shanghai, China), were housed in standard polypropylene cages. The animals were maintained on a standard 12-h light/dark cycle (lights on at 7:00 a.m. and lights off at 7:00 p.m.), in a temperature-controlled environment (23 ± 2 °C), with access to water and chow ad libitum (high fat diet or standard diet). The experiment and procedures were conducted in accordance to the Laboratory Animal Care Committee at China

HFD-induced steatosis with VLDL overproduction in liver is associated with 5-HT 2 receptors

To examine the effect of 5-HT on the hepatic steatosis and VLDL assembly, SCD or HFD-fed rats were exposed to 5-HT. And, in order to confirm the specific role of 5-HT₂R in HFD-induced hepatic steatosis and VLDL assembly, SCD or HFD-fed, 5-HT-exposed rats, and HFD-fed rats were treated with Sar. Both body weight (Fig. 1A, left) and food intake (Fig. 1A, middle) (increased calorie intake) (Fig. 1A) were increased by HFD, and liver weight to body weight ratio, i.e. HI (Fig. 1A, right), was also

Discussion

The present study examined the contribution of 5-HT and 5-HT₂R in the HFD-induced hepatic steatosis and VLDL overproduction. It has been reported that 5-HT is a key factor in the l-tryptophan-aggravated hepatic steatosis induced by high fat and high fructose diet in mice [8]. Our study demonstrated that HFD-induced abnormality of hepatic lipid metabolism is also directly mediated by up-regulated 5-HT₂R with 5-HT synthesis in the hepatocytes, while the effect of 5-HT on appetite may be minor for

Authors’ contribution

All authors contributed to the design and conduct of the study, data collection and analysis, data interpretation and manuscript writing.

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

There are no conflicts of interest.

Acknowledgments

The authors are grateful to Professor Rong Hu (China Pharmaceutical University) for her contribution in manuscript revision, and Jun Yang, a physician of pathology department in Nanjing Drum Tower Hospital, China, for his contribution in histopathological examination.

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¹: These authors contributed equally to this work.

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Original Article5-HT 2 receptor mediates high-fat diet-induced hepatic steatosis and very low density lipoprotein overproduction in rats

Summary

Background

Materials and methods

Results

Conclusions

Introduction

Section snippets

Animal experiment

HFD-induced steatosis with VLDL overproduction in liver is associated with 5-HT 2 receptors

Discussion

Authors’ contribution

Funding

Conflicts of interest

Acknowledgments

Pharmacol Biochem Behav

Gastroenterology

J Biol Chem

Thromb Res

J Biol Chem

J Biol Chem

Mol Cell Endocrinol

J Hepatol

Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives

Cell Mol Life Sci

Symmetrical serotonin release during asymmetrical slow-wave sleep: implications for the neurochemistry of sleep-waking states

J Neurosci

Role of serotonin 5-HT(3) receptors in intestinal inflammation

Biol Pharm Bull

Serotonin and blood pressure regulation

Pharmacol Rev

Effects of 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists on gastrointestinal motor activity in dogs

World J Gastroenterol

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