JTP‐109192, a novel G protein‐coupled receptor 119 agonist, prevents atherosclerosis by improving hypercholesterolaemia in congenic spontaneously hyperlipidaemic mice. (4th November 2020)

• Record Type: Journal Article
• Authors: Tadaki, Hironobu; Ogawa, Naoto; Yamanaka, Masao; Motohashi, Yu; Sasase, Tomohiko; Kawai, Takashi; Toriniwa, Yasufumi; Fukuda, Sumiaki; Ogawa, Nobuya; Harada, Kazuhito; Ohta, Takeshi; Yamada, Takahisa
• Is Part Of: Clinical and experimental pharmacology and physiology. Volume 48:Number 3(2021)
• Page Start: 381
• Page End: 388
• Publication Date: 2020-11-04
• Subjects: atherosclerosis -- dyslipidaemia -- G protein‐coupled receptor 119 -- spontaneously hyperlipidaemic mouse; Clinical pharmacology -- Periodicals; Pharmacology, Experimental -- Periodicals; Physiology, Experimental -- Periodicals; Physiology, Pathological -- Periodicals; 615.1
• DOI: 10.1111/1440-1681.13423
• Languages: English
• ISSNs: 0305-1870

Abstract

Abstract: G protein‐coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L‐cells is a potential therapeutic target for the treatment of type 2 diabetes. Previously, we have reported that the GPR119 agonist JTP‐109192 improves glucose metabolism with single and repeated administration. Conversely, overexpression of the Gpr119 gene reportedly regulates cholesterol transporter expression in animal models, and a natural GPR119 agonist, oleoylethanolamide (OEA), improves atherosclerosis. Therefore, improving dyslipidaemia is considered a possible feature of GPR119 agonists. In the present study, the lipid‐lowering effect of JTP‐109192 was examined in BALB/c background spontaneously hyperlipidaemic (SHL) mice with repeated administration, once daily for 12 weeks. On repeated administration, JTP‐109192 revealed a cholesterol‐lowering effect and improved atherosclerosis following histopathological examination. With further investigation, the cholesterol‐lowering effect and subsequent antiatherosclerotic effect of JTP‐109192 was attributed to changes in intestinal cholesterol metabolism gene expression. Based on these results, JTP‐109192 represents a new potential antihypercholesterolaemic agent for the treatment of dyslipidaemia. Abstract : GPR119 agonist, JTP‐109192 decreases plasma total cholesterol and increases HDL cholesterol levels by altering intestinal cholesterol metabolism gene expression that may modify atherosclerosis.