Swaminath Gayathri
Amgen Inc., South San Francisco, CA 94080, USA.
Arch Pharm (Weinheim). 2008 Dec;341(12):753-61. doi: 10.1002/ardp.200800096.
G-protein-coupled receptors (GPCRs) respond to various physiological ligands such as photons, ions, and small molecules that include amines, fatty acids, and amino acids to peptides, proteins and steroids. Therefore, this family of proteins represents an attractive target for biopharmaceutical research. The physiological role of fatty acids and other lipid molecules as important signal mediators is well studied in various metabolic pathways. Acute administration of free fatty acids (FFAs) stimulates insulin release. Conversely, chronic exposure to high levels of free fatty acids leads to impairment of beta cell function and lipotoxicity. However, the receptors through which these fatty acids and lipids act were unknown, until the identification of fatty acid binding receptors: GPR40, GPR41, GPR43, and GPR119. Based on their tissue-expression profile, and pharmacologic analysis, the fatty acid binding receptors along with lipid binding receptor GPR119 are linked to diabetes and obesity. They play a critical role in the metabolic regulation of insulin release and glucose homeostasis. In this review, the mechanism of receptor activation, pharmacology, and the physiological functions of the fatty acid binding receptors will be discussed.
G蛋白偶联受体（GPCRs）可对多种生理配体作出反应，这些配体包括光子、离子以及小分子（如胺类、脂肪酸、氨基酸）、肽类、蛋白质和类固醇。因此，这类蛋白质家族是生物制药研究的一个有吸引力的靶点。脂肪酸和其他脂质分子作为重要信号介质的生理作用在各种代谢途径中得到了充分研究。急性给予游离脂肪酸（FFAs）可刺激胰岛素释放。相反，长期暴露于高水平的游离脂肪酸会导致β细胞功能受损和脂毒性。然而，在脂肪酸结合受体GPR40、GPR41、GPR43和GPR119被鉴定出来之前，这些脂肪酸和脂质发挥作用的受体尚不清楚。基于它们的组织表达谱和药理学分析，脂肪酸结合受体以及脂质结合受体GPR119与糖尿病和肥胖症有关。它们在胰岛素释放和葡萄糖稳态的代谢调节中起关键作用。在这篇综述中，将讨论脂肪酸结合受体的受体激活机制、药理学和生理功能。
