Hydroxycarboxylic acid receptor 2

Hydroxycarboxylic acid receptor 2 (HCA₂), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the HCAR2 gene and in rodents by the Hcar2 gene. The human HCAR2 gene is located on the long (i.e., "q") arm of chromosome 12 at position 24.31 (notated as 12q24.31). Like the two other hydroxycarboxylic acid receptors, HCA₁ and HCA₃, HCA₂ is a G protein-coupled receptor (GPCR) located on the surface membrane of cells. HCA₂ binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid), butyric acid, and niacin (also known as nicotinic acid). β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA₂. Under normal conditions, niacin's blood levels are too low to do so: it is given as a drug in high doses in order to reach levels that activate HCA₂.

β-Hydroxybutyric acid, butyric acid, and niacin have actions that are independent of HCA₂. For example: 1) β-hydroxybutyric acid activates free fatty acid receptor 3 and inhibits some histone deacetylases that regulate the expression of various genes, increase mitochondrial adenosine triphosphate production, and promote antioxidant defenses; 2) butyric acid activates free fatty acid receptor 2 and like β-hydroxybutyric acid activates free fatty acid receptor 3 and inhibits some histone deacetylases; and 3) niacin is an NAD⁺ precursor (see nicotinamide adenine dinucleotide) which when converted to NAD⁺ can alter over 500 enzymatic reactions that play key roles in regulating inflammation, mitochondrion functions, autophagy, and apoptosis. Consequently, studies examining the functions of HCA₂ based on the actions of butyric acid, β-hydroxybutyric acid, niacin, or other HCA₂ activators need to provide data indicating that they actually do so by activating HCA₂. One commonly used way to do this is to show that the activators have no or reduced effects on Hca2 gene knockout cells or animals (i.e., cells or animals that had their HCa2 genes removed or inactivated) or gene knockdown cells or animals (i.e., cells or animals that had their HCa2 genes ability to express HCA₂ greatly reduced). The studies reported here on HCA₂ activators focus on those that included experiments in Hca2 gene knockout and/or knockdown cells and animals.

Studies, done mostly in animals and the cells taken from animals or humans, show or suggest that HCA₂ functions to 1) inhibit lipolysis and 2) inhibit inflammation and thereby suppress the development of certain diseases in which inflammation contributes to their development and/or severity. These diseases include: atherosclerosis, stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, pathological pain (i.e. pain due to the abnormal activation of neurons), mastitis, hepatitis due to heavy alcohol consumption, inflammatory bowel diseases, cancer of the colon, and, possibly, psoriasis and brain damage due to heavy alcohol consumption.