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 and HCA3 homodimer and heterodimer proteins 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".
Cells and tissues expressing HCA2 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.
HCA2 activating agents 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.
HCA2's function in lipolysis 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.
HCA2's functions in various diseases Atherosclerosis 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.
Stroke Stroke is the development of persistent brain disfunction caused by the interruption of blow flow and subsequent damage to the brain. The inflammation that develops in damaged areas of the brain causes further brain damage. Studies have reported that HCA2 reduces the inflammation and thereby the extent of brain damage in animal models of stroke. Mice that had a distal portion of their middle cerebral arteries occluded were treated with either β-hydroxybutyric acid or niacin shortly before and up to 48 hours after occluding the artery. β-Hydroxybutyric acid-treated mice had less damaged brain tissue and better performances in corner testing (i.e., control mice but not β-hydroxybutyric acid-treated mice tended to turn toward the side opposite the damaged brain site). β-Hydroxybutyric acid did not reduce the brain damage or improve corner test performance in Hca2 gene knockout mice. Niacin likewise reduced the size of the damaged brain site in normal but not in Hca2 gene knockout mice. And, mice feed a ketogenic diet for 14 days (which increased their plasma levels of β-hydroxybutyric acid) also had reductions in the size of their brains' damaged sites. The diet had no such effect inHca2 gene knockout mice. Further studies indicated that the effect of niacin in reducing the size of damage brain sites involved the stimulation of HCA2-bearing monocytes and/or macrophages to produce prostaglandin D2. (Prostaglandin D2 has anti-inflammatory actions.) Finally, several other studies, while not examining Hcar2 gene knockout or knockdown animals, reported that β-hydroxybutyric acid, niacin. monomethyl fumarate, and dimethyl fumarate reduced the inflammation, tissue damage, and/or symptoms in middle cerebral artery occlusion animal models of stroke. These results indicate that HCA2 reduces the clinical consequences of stroke in rodents and support further studies that may lead to the development of novel treatments for stroke in humans.
Alzheimer's disease