Hydroxycarboxylic Acid Receptor (HCAR)

The hydroxycarboxylic acid (HCA) receptor family consists of three members, HCA1, HCA2, and HCA3, also known as GPR81, GPR109A, and GPR109B, respectively, which are encoded by closely related genes. The physiological ligands of HCA receptors are key metabolic intermediates whose local and systemic levels reflect particular metabolic states. Lactic acid, the end product of glycolysis, activates HCA1, whereas the ketone body 3-hydroxy-butyric acid [b-hydroxybutyrate (b-HB)] and the b-oxidation intermediate 3-hydroxy-octanoic acid activate HCA2 and HCA3, respectively. In addition, HCA2 is also activated by butyric acid. All three HCA receptors are highly expressed in white and brown adipocytes. Expressions of HCA1 and HCA2 have been shown to increase during differentiation of adipocytes from preadipocytes as well as after activation of peroxisome proliferator-activated receptor-gamma. Both high-fat diet (HFD) feeding and exposure to various inflammatory stimuli result in decreased expression of HCA1 in the adipose tissue. While HCA2 expression in the adipose tissue is also decreased after HFD feeding, inflammatory stimuli increase expression of HCA2. During the past decade, it has become clear that HCA receptors help to maintain homeostasis under changing metabolic and dietary conditions, by controlling metabolic, immune, and other body functions. Work based on genetic mouse models and synthetic ligands of HCA receptors has, in addition, shown that members of this receptor family can serve as targets for the prevention and therapy of diseases such as metabolic and inflammatory disorders.