Hydroxycarboxylic Acid Receptor Antibodies

The hydroxycarboxylic acid receptor family comprises three class A G protein-coupled receptors, HCA₁ (GPR81), HCA₂ (GPR109A), and HCA₃ (GPR109B), encoded by HCAR1, HCAR2, and HCAR3, respectively. Their endogenous agonists include lactate for HCA₁, the ketone body β-hydroxybutyrate for HCA₂, and the fatty acid oxidation intermediate 3-hydroxyoctanoate for HCA₃. All three receptors couple predominantly to Gi/o, inhibiting adenylyl cyclase and reducing intracellular cAMP. They are expressed in adipose tissue, where activation can suppress lipolysis and link metabolite availability to energy storage. HCA₂ and HCA₃ are also expressed in immune cell populations, while HCA₁ has been detected in the brain and other tissues. HCA₂ signaling has been implicated in the regulation of inflammation, whereas the physiological functions of HCA₃ remain less well defined. Receptor desensitization, β-arrestin recruitment, and internalization vary with the receptor subtype and ligand. Niacin and acipimox are clinically used HCA₂ agonists for selected lipid disorders, and monomethyl fumarate, the active metabolite of dimethyl fumarate, also activates HCA₂. No HCA₁- or HCA₃-selective drug is currently approved for therapeutic use.