beta-Hydroxybutyric acid

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]

butyrate→butyryl-CoA→crotonyl-CoA→β-hydroxybutyryl-CoA→poly-β-hydroxybutyrate→D-β-(D-β-hydroxybutyryloxy)-butyrate→D-β-hydroxybutyrate

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 when blood glucose is low.[5] 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.

Leucine metabolism in humans L-Leucine Branched-chain amino acid aminotransferase α-Ketoglutarate Glutamate Glutamate Alanine Pyruvate Muscle: α-Ketoisocaproate (α-KIC) Liver: α-Ketoisocaproate (α-KIC) Branched-chain α-ketoacid dehydrogenase (mitochondria) KIC-dioxygenase (cytosol) Isovaleryl-CoA β-Hydroxy β-methylbutyrate (HMB) Excreted in urine (10–40%) HMB-CoA β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) β-Methylcrotonyl-CoA (MC-CoA) β-Methylglutaconyl-CoA (MG-CoA) CO2 CO2 O2 CO2 H2O CO2 H2O (liver) HMG-CoA lyase Enoyl-CoA hydratase Isovaleryl-CoA dehydrogenase MC-CoA carboxylase MG-CoA hydratase HMG-CoA reductase HMG-CoA  synthase β-Hydroxybutyrate dehydrogenase Mevalonate pathway Thiolase Unknown enzyme β-Hydroxybutyrate Acetoacetyl-CoA Acetyl-CoA Acetoacetate Mevalonate Cholesterol [note 1] Acetoacetate, the metabolic precursor of β-hydroxybutyrate, is a metabolite of fatty acids, ketogenic amino acids such as leucine[8] and isoleucine,[8] and β-hydroxy β-methylbutyrate.

D-β-Hydroxybutyric acid, along with butyric acid, are the two primary endogenous agonists of hydroxycarboxylic acid receptor 2 (HCA₂), a G_i/o-coupled GPCR.[1][2][9]

β-Hydroxybutyric acid is able to cross the blood-brain-barrier into the central nervous system.[10] Levels of β-hydroxybutyric acid increase in the liver, heart, muscle, brain, and other tissues with exercise, calorie restriction, fasting, and ketogenic diets.[10] The compound has been found to act as a histone deacetylase (HDAC) inhibitor.[10] Through inhibition of the HDAC class I isoenzymes HDAC2 and HDAC3, β-hydroxybutyric acid has been found to increase brain-derived neurotrophic factor (BDNF) levels and TrkB signaling in the hippocampus.[10] Moreover, a rodent study found that prolonged exercise increases plasma β-hydroxybutyrate concentrations, which induces promoters of the BDNF gene in the hippocampus.[10] These findings may have clinical relevance in the treatment of depression, anxiety, and cognitive impairment.[10]

In epilepsy patients on the ketogenic diet, blood β-hydroxybutyrate levels correlate best with degree of seizure control. The threshold for optimal anticonvulsant effect appears to be approximately 4 mmol/L.[11]

β-Hydroxybutyric acid is the precursor to polyesters, which are biodegradable plastics. This polymer, poly(3-hydroxybutyrate), is also naturally produced by the bacteria Alcaligenes eutrophus.[12]

β-Hydroxybutyrate can be extracted from poly(3-hydroxybutyrate) by acid hydrolysis.[13]

The concentration of β-hydroxybutyrate in blood plasma is measured through a test that uses β-hydroxybutyrate dehydrogenase, with NAD⁺ as an electron-accepting cofactor. The conversion of β-hydroxybutyrate to acetoacetate, which is catalyzed by this enzyme, reduces the NAD⁺ to NADH, generating an electrical change; the magnitude of this change can then be used to extrapolate the amount of β-hydroxybutyrate in the sample.

• Hydroxybutyric acid
• Ketogenesis
• Gamma-Hydroxybutyric acid
• β-Hydroxy β-methylbutyric acid (HMB)