Blad Clara C, Ahmed Kashan, IJzerman Ad P, Offermanns Stefan
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Adv Pharmacol. 2011;62:219-50. doi: 10.1016/B978-0-12-385952-5.00005-1.
The hydroxy-carboxylic acid (HCA) receptors HCA(1), HCA(2), and HCA(3) were previously known as GPR81, GPR109A, and GPR109B, respectively, or as the nicotinic acid receptor family. They form a cluster of G protein-coupled receptors with high sequence homology. Recently, intermediates of energy metabolism, all HCAs, have been reported as endogenous ligands for each of these receptors. The HCA receptors are predominantly expressed on adipocytes and mediate the inhibition of lipolysis by coupling to G(i)-type proteins. HCA(1) is activated by lactate, HCA(2) by the ketone body 3-hydroxy-butyrate, and HCA(3) by hydroxylated β-oxidation intermediates, especially 3-hydroxy-octanoic acid. Both HCA(2) and HCA(3) are part of a negative feedback loop which keeps the release of fat stores in check under starvation conditions, whereas HCA(1) plays a role in the antilipolytic (fat-conserving) effect of insulin. HCA(2) was first discovered as the molecular target of the antidyslipidemic drug nicotinic acid (or niacin). Many synthetic agonists have since been designed for HCA(2) and HCA(3), but the development of a new, improved HCA-targeted drug has not been successful so far, despite a number of clinical studies. Recently, it has been shown that the major side effect of nicotinic acid, skin flushing, is mediated by HCA(2) receptors on keratinocytes, as well as on Langerhans cells in the skin. In this chapter, we summarize the latest developments in the field of HCA receptor research, with emphasis on (patho)physiology, receptor pharmacology, major ligand classes, and the therapeutic potential of HCA ligands.
羟基羧酸（HCA）受体HCA(1)、HCA(2)和HCA(3)以前分别被称为GPR81、GPR109A和GPR109B，或属于烟酸受体家族。它们形成了一组具有高度序列同源性的G蛋白偶联受体。最近，能量代谢的中间产物，即所有的HCA，已被报道为这些受体各自的内源性配体。HCA受体主要在脂肪细胞上表达，并通过与G(i)型蛋白偶联来介导对脂肪分解的抑制作用。HCA(1)由乳酸激活，HCA(2)由酮体3-羟基丁酸激活，HCA(3)由羟基化的β-氧化中间产物，尤其是3-羟基辛酸激活。HCA(2)和HCA(3)都是负反馈回路的一部分，该回路在饥饿条件下控制脂肪储备的释放，而HCA(1)在胰岛素的抗脂解（脂肪保存）作用中发挥作用。HCA(2)最初被发现是抗血脂异常药物烟酸（或尼克酸）的分子靶点。此后，人们设计了许多针对HCA(2)和HCA(3)的合成激动剂，但尽管进行了多项临床研究，开发一种新的、改进的HCA靶向药物迄今尚未成功。最近，研究表明烟酸的主要副作用皮肤潮红是由角质形成细胞以及皮肤中朗格汉斯细胞上的HCA(2)受体介导的。在本章中，我们总结了HCA受体研究领域的最新进展，重点介绍（病理）生理学、受体药理学、主要配体类别以及HCA配体的治疗潜力。
