HCA2 Receptor and Ketone Body Signaling of β-Hydroxybutyrate as an Endogenous Immunometabolic Regulator in Neuro-Cardiac Protection

The discovery that the ketone body β-hydroxybutyrate functions as an endogenous ligand for the hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1, has fundamentally transformed the scientific understanding of ketone biology by establishing a direct molecular link between metabolic state and immune function that operates independently of β-hydroxybutyrate’s classical role as an energy substrate during glucose scarcity, and this article presents a comprehensive examination of the molecular mechanisms by which β-hydroxybutyrate activates HCA2 to provide simultaneous protection against neuroinflammation and cardiac oxidative stress through coordinated effects on microglial cells in the central nervous system and macrophages in the cardiovascular system. The HCA2 receptor is a class A G-protein-coupled receptor encoded on chromosome 12q24.31 that couples preferentially to inhibitory G proteins of the Gi/o family and is expressed on microglia in the brain parenchyma, cardiac macrophages including both resident CCR2-negative and infiltrating CCR2-positive populations, coronary artery endothelial cells, and vascular smooth muscle cells, with crystallographic studies revealing that arginine 111 in transmembrane domain 3 forms a critical ionic interaction with the carboxylate group of β- hydroxybutyrate that is essential for ligand recognition and receptor activation. The binding affinity of β-hydroxybutyrate for HCA2 is approximately 700 micromolar, which is physiologically significant because this relatively low affinity ensures that the receptor remains inactive at baseline β-hydroxybutyrate concentrations of approximately 100 micromolar but becomes progressively activated as concentrations rise to two to five millimolar during fasting, prolonged exercise, or exogenous ketone supplementation, effectively creating a metabolic rheostat that engages protective mechanisms in proportion to the degree of metabolic stress.