Biological Roles and Therapeutic Potential of Hydroxy-Carboxylic Acid Receptors

Kashan Ahmed

doi:10.3389/fendo.2011.00051

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 HCA1 receptor (GPR81) is activated by the glycolytic metabolite 2-hydroxy-propionic acid (lactate), the HCA2 receptor is activated by the ketone body 3-hydroxy-butyric acid, and the HCA3 receptor (GPR109B) is a receptor for the β-oxidation intermediate 3-hydroxy-octanoic acid. While HCA1 and HCA2 receptors are present in most mammalian species, the HCA3 receptor is exclusively found in humans and higher primates. HCA receptors are expressed in adipose tissue and mediate anti-lipolytic effects in adipocytes through Gi-type G protein-dependent inhibition of adenylyl cyclase. HCA2 and HCA3 inhibit lipolysis during conditions of increased β-oxidation such as prolonged fasting, whereas HCA1 mediates the anti-lipolytic effects of insulin in the fed state. As HCA2 is a receptor for the established anti-dyslipidemic drug nicotinic acid, HCA1 and HCA3 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.

Highlights

G protein-coupled receptors (GPCRs) form one of the largest protein families and are encoded by about 800 genes in mammalian organisms (Lander et al, 2001; Venter et al, 2001; Pierce et al, 2002)
PERSPECTIVES In 2003, the HCA2 receptor was identified as the target of the anti-dyslipidemic drug nicotinic acid and various synthetic agonists of HCA2 have been developed since
The physiological ligands of HCA receptors remained elusive until recently, when hydroxy-carboxylic acids have been identified as endogenous agonists of HCA1, HCA2, and HCA3 (Table 1)

Summary

INTRODUCTION

G protein-coupled receptors (GPCRs) form one of the largest protein families and are encoded by about 800 genes in mammalian organisms (Lander et al, 2001; Venter et al, 2001; Pierce et al, 2002). Another study described lactate as a specific agonist of the HCA1 receptor with EC50 values for lactate-induced binding of GTPγS and FIGURE 2 | Model of the physiological function of the HCA1 receptor. Because endogenous plasma levels of nicotinic acid are too low to activate HCA2, it is unlikely that nicotinic functions as a physiological ligand of the HCA2 receptor (Gille et al, 2008). HCA3 Despite its pronounced homology to HCA2, the HCA3 receptor is not activated by the HCA2-agonists nicotinic acid and 3-hydroxybutyrate and has remained as an orphan receptor until recently, when 2- and 3-hydroxy medium chain fatty acids were described as the first endogenously occurring HCA3-specific agonists (Ahmed et al, 2009a). Some data suggest expression of HCA3 receptor at the apical membrane of human colonic epithelium by using antibodies directed at HCA3 (Thangaraju et al, 2009)

G PROTEIN COUPLING AND SIGNALING

Findings

CONCLUSION AND FUTURE PERSPECTIVES