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.

HCA₂ is commonly formed and regarded as a homodimer, i.e. to be composed of two adjoined HCA₂ proteins. However, a heterodimer composed of the HCA₂ protein adjoined to the HCA₃ protein has been detected in human embryonic kidney HEK 293 cells. The human HCAR2 and HCAR3 genes sit next to each other on chromosome 12 at position 24.31 and have an amino acid sequence homology greater than 95%. While there appears to be no significant difference in the responses triggered by activation of cells expressing the HCA₂ homodimer versus the HCA₂/HCA₃ heterodimer proteins, more studies are needed to confirm this. Furthermore: 1) HCA₂ and HCA₁ are found in most mammalian species but HCA₃ is found only in higher primates and 2) monodimeric HCA₂ and HCA₃ proteins may show very different ligand sensitivities, e.g., niacin binds to and activates HCA₂ but does not or only weakly binds to and activates HCA₃. Studies on HCA₂ in human cells and tissues have not determined the extent to which these cells and tissues also express HCA₃ and form HCA₃-HCA₃ heterodimers. The studies cited here may need to be revised if future studies find that HCA₂-HCA₃ heterodimers are involved in the effects of "HCA₂ activators".

HCA₂ is expressed by: 1) certain cells in the immune system, e.g., neutrophils, monocytes, macrophages, dermal dendritic cells, and lymphocytes; 2) cells in the small intestine and colon epithelum that face the intestinal lumen; 3) the skin's epithelial cells, keratinocytes, and Langerhans cells; 4) brown and white adipose tissue fat cells; 5) cells in the mammary gland's epithelium; 6) hepatocytes; 7) multinucleated osteoclasts in bone tissues; 8) kidney podocytes; and 9) cells in the nervous system, e.g., microglia cells in the brain's cerebral cortex and hippocampus, cells in the eye's retinal pigment epithelium, the astrocytes and neurons in the brain's rostral ventrolateral medulla, and the peripheral nervous system's Schwann and satellite glial cells.

In addition to butyric acid, β-hydroxybutyric acid, and niacin, the following agents have been reported to activate HCA₂: monomethyl fumarate, dimethyl fumarate (dimethyl fumarate is a prodrug, i.e. it does not directly activate HCA₂ but is rapidly converted in animal intestines to monomethyl fumarate), Acifran (Acifran also binds to HCA₃ but with less affinity for it than for HCA₃), Acipimox, SCH 900271, MK-6892, MK-1903, GSK256073, and N2L.

Lipolysis is the metabolic pathway in which triglycerides are hydrolyzed, i.e., enzymatically broken down, into their component free fatty acids and glycerol. The activation of this pathway leads fat cells to release the newly freed fatty acids into the circulation and thereby raises serum free fatty acid levels; the inhibition of this lipolysis leads to falls in serum free fatty acid levels. The intravascular injection of niacin into control mice rapidly reduced their serum fatty acid levels but did not do so in Hcar2 gene knockout mice. Thus, HCA₂ functions to inhibit lipolysis and lower serum fatty acid levels in mice. Niacin likewise inhibits lipolysis to lower free fatty acid plasma levels in humans. Furthermore, the HCA₂-activating drug, MK-1903, when taken orally by healthy volunteers in phase 1 and 2 clinical trials, dramatically lowered their plasma free fatty acids levels. Like niacin, flushing was the drug's only major adverse effect. Unlike niacin, however, MK-1903 had far less effects than niacin on the plasma levels of triglycerides and HDL-c] (i.e., cholesterol-associated High density lipoprotein) which are niacin's therapeutic targets for treating primary hyperlipidemia and hypertriglyceridemia. These findings suggest but need further studies to determine if niacin and Mk-1903 inhibit lipolysis in humans by activating HCA₂. Studies suggest that HCA₁ and, possibly, HCA₃ also inhibit lipolysis.

Atherosclerosis is a chronic inflammatory arterial disease that can cause the narrowing or occlusion of arteries and thereby various cardiovascular diseases such as heart attacks and strokes. In a murine ApoE−/− model of atherosclerosis, mice were fed a cholesterol‐rich (i.e., atherosclerosis-promoting) diet concurrently with β-hydroxybutyric acid, nicotine, or salt water daily for 9 weeks. The aortas of β-hydroxybutyric acid-treated and niacin-treated mice had far less histological evidence of atherosclerosis (i.e., less atherosclerotic plaques, lipid depositions, and infiltrating M1 inflammation-promoting macrophages) than salt water-treated mice. β-Hydroxybutyric acid-fed mice also had significantly lower blood plasma levels of three pro-inflammatory cytokines, tumor necrosis factor-α, interleukin-6, and interleukin-1β, than salt water-treated mice. Further studies found that 1) β-hydroxybutyric acid inhibited lipopolysaccharide-simulated maturation of normal bone marrow‐derived macrophages to M1 macrophages but did not do so in macrophages taken from the bone marrows of Hcar2 gene knockout mice and 2) mice constructed to have Hcar2 gene knockout but no normal bone marrow cells who were treated with β-hydroxybutyric acid had significantly more evidence of arterial inflammation and atherosclerosis than β-hydroxybutyric acid-treated mice who had normal bone marrow cells. These results indicate that the anti-inflammatory and anti-atherosclerotic effects of β-hydroxybutyric acid in ApoE−/− mice depend on bone‐marrow‐derived HCA₂-expressing cells, possibly M1 macrophages. Further studies are needed to determine if HCA₂ acts to suppress the development and/or progression of human atherosclerosis.