Biological roles and therapeutic potential of hydroxy-carboxylic Acid receptors

Abstract

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.

Keywords: 3-hydroxy-octanoic acid; G protein-coupled receptors; GPR109A; GPR109B; GPR81; deorphanization; hydroxy-carboxylic acid receptors; lactate; nicotinic acid.

Figure 1

Schematic representation of the chromosomal location of genes encoding hydroxy-carboxylic acid (HCA) receptors. Protein-coding sequences are shown by filled rectangles. Adapted from Ensembl Genome Browser.

Figure 2

Model of the physiological function of the HCA₁ receptor. During feeding, adipocytes can produce and release significant amounts of lactate, a process stimulated by insulin-induced glucose uptake. Lactate activates HCA₁ receptors on adipocytes in an autocrine and paracrine fashion and decreases intracellular cAMP levels through G_i/G_o-dependent inhibition of adenylyl cyclase. This leads together with the insulin-dependent activation of PDE3B to increased degradation and decreased formation of intracellular cAMP resulting in an inhibition of lipolysis. Thus, the lactate receptor HCA₁ mediates the anti-lipolytic of insulin effects during the transition from the fed to the fasted state and thereby helps to preserve endogenous energy stores when food-derived nutrients are abundant. AC, adenylyl cyclase; IR, insulin receptor; PDE3B, phosphodiesterase 3B; PI3K, phosphatidylinositol-3-kinase; PKA, protein kinase A.

Figure 3

Model of the physiological functions of HCA₂ and HCA₃ receptors. During conditions of increased β-oxidation rates (e.g., during fasting), plasma concentrations of the ketone body 3-hydroxybutyrate and β-oxidation intermediates, in particular 3-hydroxy-octanoate, reach levels sufficient to activate their respective receptors HCA₂ and HCA₃, which then mediate an inhibition of adipocyte lipolysis through G_i/G_o-dependent inhibition of adenylyl cyclase. Thereby, HCA₂ and HCA₃ regulate lipolysis in a negative feedback manner, and counter-regulate pro-lipolytic stimuli in order to economize triglyceride utilization and avoid a waste of energy substrates. AC, adenylyl cyclase; β-AR, β-adrenergic receptor; PKA, protein kinase A; TG, triglyceride; HSL, hormone-sensitive lipase; ATGL, adipocyte triglyceride lipase; FFA, free fatty acids; 3-OHB, 3-hydroxybutyrate; AcAc, acetoacetate.