Covington D K, Briscoe C A, Brown A J, Jayawickreme C K
Department of Molecular Pharmacology, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Biochem Soc Trans. 2006 Nov;34(Pt 5):770-3. doi: 10.1042/BST0340770.
Recent deorphanization efforts have paired the G-protein-coupled receptors GPR40, GPR41 and GPR43 with fatty acids as endogenous ligands. While carboxylic acids have been historically known to serve as fuel sources and biomarkers of disease, these studies demonstrate that fatty acids can act as signalling molecules at the cell-surface level. This receptor subfamily shares approx. 30% identity among members, with some limited cross-over between ligand activities. Generalized expression patterns within the pancreatic beta-cell, adipose depots and the gastrointestinal tract infer involvement in energy source recognition, absorption, storage and/or metabolism. GPR40, activated by medium and long-chain fatty acids, has been shown to potentiate insulin secretion at the beta-cell, and has been hypothesized to participate in the detrimental effects of chronic fatty acid exposure on beta-cell function. GPR41 and GPR43 have been reported to stimulate leptin release and adipogenesis respectively via activation by short-chain fatty acids. These common themes implicate GPR40, GPR41 and GPR43 in playing significant roles in metabolic diseases, such as diabetes, obesity and the metabolic syndrome.
最近的去孤儿化研究工作已将G蛋白偶联受体GPR40、GPR41和GPR43与脂肪酸作为内源性配体配对。虽然羧酸一直以来被认为是疾病的能量来源和生物标志物，但这些研究表明，脂肪酸在细胞表面水平上可作为信号分子。该受体亚家族成员之间约有30%的同源性，配体活性之间存在一些有限的交叉。胰腺β细胞、脂肪储存部位和胃肠道内的普遍表达模式表明其参与能量源识别、吸收、储存和/或代谢。由中链和长链脂肪酸激活的GPR40已被证明可增强β细胞的胰岛素分泌，并被推测参与慢性脂肪酸暴露对β细胞功能的有害影响。据报道，GPR41和GPR43分别通过短链脂肪酸的激活来刺激瘦素释放和脂肪生成。这些共同的特点表明GPR40、GPR41和GPR43在诸如糖尿病、肥胖症和代谢综合征等代谢性疾病中发挥着重要作用。
