Institute of Molecular Systems Biology, Swiss Federal Institute of Technology Zurich, Switzerland.
Front Endocrinol (Lausanne). 2011 Oct 25;2:51. doi: 10.3389/fendo.2011.00051. eCollection 2011.
In the recent past, deorphanization studies have described intermediates of energy metabolism to activate G protein-coupled receptors and to thereby regulate metabolic functions. GPR81, GPR109A, and GPR109B, formerly known as the nicotinic acid receptor family, are encoded by clustered genes and share a high degree of sequence homology. Recently, hydroxy-carboxylic acids were identified as endogenous ligands of GPR81, GPR109A, and GPR109B, and therefore these receptors have been placed into a novel receptor family of hydroxy-carboxylic acid (HCA) receptors. The HCA(1) receptor (GPR81) is activated by the glycolytic metabolite 2-hydroxy-propionic acid (lactate), the HCA(2) receptor is activated by the ketone body 3-hydroxy-butyric acid, and the HCA(3) receptor (GPR109B) is a receptor for the β-oxidation intermediate 3-hydroxy-octanoic acid. While HCA(1) and HCA(2) receptors are present in most mammalian species, the HCA(3) receptor is exclusively found in humans and higher primates. HCA receptors are expressed in adipose tissue and mediate anti-lipolytic effects in adipocytes through G(i)-type G protein-dependent inhibition of adenylyl cyclase. HCA(2) and HCA(3) inhibit lipolysis during conditions of increased β-oxidation such as prolonged fasting, whereas HCA(1) mediates the anti-lipolytic effects of insulin in the fed state. As HCA(2) is a receptor for the established anti-dyslipidemic drug nicotinic acid, HCA(1) and HCA(3) also represent promising drug targets and several synthetic ligands for HCA receptors have been developed. In this article, we will summarize the deorphanization and pharmacological characterization of HCA receptors. Moreover, we will discuss recent progress in elucidating the physiological and pathophysiological role to further evaluate the therapeutic potential of the HCA receptor family for the treatment of metabolic disease.
在最近的过去，去孤儿化研究已经描述了能量代谢的中间体来激活 G 蛋白偶联受体，从而调节代谢功能。GPR81、GPR109A 和 GPR109B，以前称为烟酸受体家族，由簇状基因编码，具有高度的序列同源性。最近，羟基羧酸被鉴定为 GPR81、GPR109A 和 GPR109B 的内源性配体，因此这些受体被归入一种新型的羟基羧酸 (HCA) 受体家族。HCA(1)受体 (GPR81) 被糖酵解代谢物 2-羟丙酸 (乳酸) 激活，HCA(2)受体被酮体 3-羟丁酸激活，HCA(3)受体 (GPR109B) 是 β-氧化中间产物 3-羟辛酸的受体。虽然 HCA(1)和 HCA(2)受体存在于大多数哺乳动物物种中，但 HCA(3)受体仅存在于人类和高等灵长类动物中。HCA 受体在脂肪组织中表达，并通过 G(i)型 G 蛋白依赖性抑制腺苷酸环化酶来介导脂肪细胞的抗脂肪分解作用。HCA(2)和 HCA(3)在增加 β-氧化的情况下抑制脂肪分解，如长时间禁食，而 HCA(1)在进食状态下介导胰岛素的抗脂肪分解作用。由于 HCA(2)是一种已被证实的抗血脂药物烟酸的受体，HCA(1)和 HCA(3)也代表了有前途的药物靶点，并且已经开发了几种 HCA 受体的合成配体。在本文中，我们将总结 HCA 受体的去孤儿化和药理学特征。此外，我们将讨论阐明生理和病理生理作用的最新进展，以进一步评估 HCA 受体家族在治疗代谢疾病方面的治疗潜力。
