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  • br Experimental procedure br Funding The present study was


    Experimental procedure
    Funding The present study was supported by the Grant Russian Foundation for basic research (project no. 16-04-01517).
    Introduction 5-HT, a monoaminergic neurotransmitter, is synthesised from l-tryptophan catalysed by the enzymes tryptophan hydroxylase (Tph) and aromatic amino SCH 39166 hydrobromide 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 [4–6]. 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 146μg/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-HT1, 3, 4, 5, 6, 7Rs 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-HT2AR and 5-HT2BR, 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.
    Materials and methods
    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 controlling hepatic lipid metabolism, because in the present study 5-HT treatment decreased food intake and body weight but increased liver weight to body weight ratio, hepatic TG and VLDL production with steatosis in both the SCD and HFD-fed rats. Many studies have shown that increased TG and VLDL synthesis in the liver is of primary features for non-alcoholic fatty liver disease (NAFLD) induced by a long-term high-caloric diet in human, and ultimately resulting in hyperlipidemia and IR [17]. GPAT1 is a rate-limiting enzyme in the initial step of TG synthesis [18] while MTTP plays an essential and rate-limiting role in forming VLDL through facilitating the translocation of ApoB100 across the endoplasmic reticulum and transferring the newly-synthesised cholesterol ester and TG to ApoB100 [19]. VLDL is merely synthesised in the hepatocytes and secreted from the liver into the blood, resulting in high levels of VLDL-c and LDL-c with hyperlipidemia [20]. In the present study, we found that up-regulation of hepatic GPAT1 and MTTP with hepatocellular lipid accumulation, and increased contents of TG and VLDL were accompanied by up-regulation of 5-HT synthesis and 5-HT2A, 2BR expression in the liver of HFD-fed rats and PA-exposed HepG2 cells, while both HFD effects in vivo and PA effects in vitro could be strongly abolished by Sar treatment, a broad-spectrum antagonist of 5-HT2R, suggesting that 5-HT2R is very important in mediating HFD feeding-induced abnormality of hepatic lipid metabolism. Free fatty acid (FFA) in blood is very important for HFD-induced ectopic fatty accumulation in the liver and skeletal muscle [21]. We also observed that Sar treatment partly but mildly reversed HFD or/and 5-HT-induced increase in serum FFAs. However, we speculate that Sar's effect on inhibition of serum FFA level is minor in the suppressing HFD-caused TG and VLDL overproduction in the liver, while it is major effect is to directly block 5-HT2A and 2B receptor on the hepatocellular membrane, resulting in a direct inhibition on 5-HT2R-mediated TG and VLDL synthesis, which was confirmed in the PA-treated HepG2 cells in vitro. In addition, we found that 5-HT also significantly up-regulated expression of GPAT1 and MTTP both in rat liver and in HepG2 cells, while its effect on inducing hepatocellular lipid accumulation was mild. The reason, we speculate, was a deficiency of fatty acid, a precursor of TG synthesis in the 5-HT-treaed rats or cells. HFD-caused hepatic inflammation, which showed an increased hepatic TNF-α level, was reversed by Sar, suggesting that 5-HT2R also involves in HFD-evoked hepatic inflammation.