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  • br Introduction Nicotinic acid has been used clinically for

    2021-11-30


    Introduction Nicotinic CID 755673 has been used clinically for more than 50 years [1] since it has anti-atherogenic effects, including the ability to reduce triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), and elevate high-density lipoprotein cholesterol (HDL-C) [2]. Nicotinic acid administration rapidly lowers non-esterified fatty acid (NEFA) levels, many literature described this was the core mechanism by which nicotinic acid provides its effect on lipids metabolism. In particular, a lowering of the NEFA substrate limits hepatic TG synthesis and TG secretion as very low density lipoprotein (VLDL) from the liver [[1], [2], [3], [4]]. Although the proposed mechanism requires further investigation, reduced VLDL production is believed to be one of the mechanism to cause other anti-dyslipidemic effects, including LDL-C reduction and HDL-C elevation [2,4]. GPR109A, a G-protein-coupled receptor located mainly on adipocyte cell membranes, has been identified as the molecular target for nicotinic acid [[5], [6], [7]] and mediator of NEFA reduction [5]. As a mechanism of NEFA-lowering, it is recognized that activation of GPR109A leads to Gi-mediated inhibition of adenylyl cyclase resulting in the reduction of activated hormone-sensitive lipase (HSL) and decrease in hydrolysis of TG to NEFA in adipose tissue [8]. GPR109A is also expressed on Langerhans cells, and stimulation of this receptor in epidermal leads to flushing symptom, well-known side effect in nicotinic acid therapy, through the production of prostaglandin D2 and prostaglandin E2 [9,10]. The contribution of GPR109A to flushing is widely accepted, however the results whether GPR109A activation leads to plasma lipid changes is controversial. To date, besides nicotinic acid analogs, acifran and acipimox, four selective and chemically designed GPR109A agonists (MK-0354, MK-1903, SCH900271 and GSK256073), have been clinically tested [[11], [12], [13], [14]]. Even though all these agonists reduced plasma NEFA levels, there seems to be variations in the plasma lipid changes [15]. Indeed, 50 mg once-daily GSK256073 treatment exhibited almost 36% reduction in plasma TG levels at 12 weeks. On the other hand, MK-0354, MK-1903 and SCH9 00271 did not show clinically meaningful reduction in TG levels. The reason for this remains unclear, but the magnitude of the pharmacodynamic effects of these GPR109A agonists may be reflective of differences in receptor potency, pharmacokinetic profiles, and/or dosing regimens used in the clinical studies. In addition, a recent study has demonstrated that the TG-lowering effect of nicotinic acid was not diminished in Gpr109a mice [12], suggesting that there was a GPR109A independent mechanism of nicotinic acid efficacy, which was different from the previous finding [5]. Thus, although there is general agreement that GPR109A has anti-lipolytic activity, the issue of whether GPR109A signaling leads to the plasma lipid changes remains unclear. The half-life of nicotinic acid is relatively short, 20–60 min [4,16], and its rapid elimination from circulating blood induces a rebound of NEFA levels [17]. In addition, the NEFA-lowering effect is lost by sustained nicotinic acid exposure [18], thereby, parameters of pharmacodynamics are largely influenced depending on the administration regimen, and the timing of blood sampling. Thus, it is difficult to correctly interpret the results of the study that investigates the in vivo physiological function of GPR109A by use of nicotinic acid as a tool of GPR109A agonist. Moreover, since the phenotype of a knock-out animal does not always show the opposite result of agonist treatment, using knock-out animals might be unsuitable for investigating the hypothesis that GPR109A activation leads to lipid changes. Instead, using a genetically overexpressing GPR109A animal is one effective way to investigate the physiological function of GPR109A in lipid metabolism in vivo, and to estimate the effects of agonist treatment of a receptor. Therefore, we created a bacterial artificial chromosome (BAC) transgenic rat expressing human GPR109A (Tg rat). Rodents are deficient in cholesteryl ester transfer protein (CETP), which has been thought to be an important mediator of LDL-C reduction and HDL-C elevation following TG reduction in nicotinic acid treatment [[19], [20], [21]]. Thus, we focused on investigating whether GPR109A signaling leads to TG lowering. Additionally, since nicotinic acid treatment decreases plasma insulin levels, and dosing of GSK256073 for 2 days decreased plasma NEFA levels and HOMA-IR scores (27–47%) [13], we examined insulin and glucose levels and the HOMA-IR index.