β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxybutyric acid is a chiral compound with two enantiomers: D-β-hydroxybutyric acid and L-β-hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature. In humans, D-β-hydroxybutyric acid is one of two primary endogenous agonists of hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor (GPCR).[1][2]
In humans, D-β-hydroxybutyrate can be synthesized in the liver via the metabolism of fatty acids (e.g., butyrate), β-hydroxy β-methylbutyrate, and ketogenic amino acids through a series of reactions that metabolize these compounds into acetoacetate, which is the first ketone body that is produced in the fasting state. The biosynthesis of D-β-hydroxybutyrate from acetoacetate is catalyzed by the β-hydroxybutyrate dehydrogenase enzyme.
Butyrate can also be metabolized into D-β-hydroxybutyrate via a second metabolic pathway that does not involve acetoacetate as a metabolic intermediate. This metabolic pathway is as follows:[3]
The last reaction in this metabolic pathway, which involves the conversion of D-β-(D-β-hydroxybutyryloxy)-butyrate into D-β-hydroxybutyrate, is catalyzed by the hydroxybutyrate-dimer hydrolase enzyme.[3]
The concentration of β-hydroxybutyrate in human blood plasma, as with other ketone bodies, increases through ketosis.[4] This elevated β-hydroxybutyrate level is naturally expected, as β-hydroxybutyrate is formed from acetoacetate. The compound can be used as an energy source by the brain and skeletal muscle when blood glucose is low.[5][6][7][8] Diabetic patients can have their ketone levels tested via urine or blood to indicate diabetic ketoacidosis. In alcoholic ketoacidosis, this ketone body is produced in greatest concentration. Ketogenesis occurs if oxaloacetate in the liver cells is depleted, a circumstance created by reduced carbohydrate intake (through diet or starvation); prolonged, excessive alcohol consumption; and/or insulin deficiency. Because oxaloacetate is crucial for entry of acetyl-CoA into the TCA cycle, the rapid production of acetyl-CoA from fatty acid oxidation in the absence of ample oxaloacetate overwhelms the decreased capacity of the TCA cycle, and the resultant excess of acetyl-CoA is shunted towards ketone body production.[citation needed]
D-β-Hydroxybutyric acid, along with butyric acid, are the two primary endogenous agonists of