| HCAR2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | HCAR2, GPR109A, HCA2, HM74a, HM74b, NIACR1, PUMAG, Puma-g, Niacin receptor 1, hydroxycarboxylic acid receptor 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:609163;MGI:1933383;HomoloGene:4391;GeneCards:HCAR2;OMA:HCAR2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is aprotein which in humans is encoded (its formation is directed) by theHCAR2gene and in rodents by theHcar2 gene.[5][6][7][8] The humanHCAR2 gene is located on the long (i.e., "q") arm ofchromosome 12 at position 24.31 (notated as 12q24.31).[9] Like the two otherhydroxycarboxylic acid receptors,HCA1 andHCA3, HCA2 is aG protein-coupled receptor (GPCR) located on thesurface membrane of cells.[5][10] HCA2 binds and thereby is activated byD-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid),butyric acid, andniacin (also known as nicotinic acid).[7][8] β-Hydroxybutyric and butyric acids are regarded as theendogenous 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.[11]
β-Hydroxybutyric acid, butyric acid, and niacin have actions that are independent of HCA2. For example:1) β-hydroxybutyric acid activatesfree fatty acid receptor 3[12] and inhibits somehistone deacetylases that regulate theexpression of various genes, increasemitochondrialadenosine triphosphate production, and promoteantioxidant defenses;[13]2) butyric acid activatesfree fatty acid receptor 2 and like β-hydroxybutyric acid activates free fatty acid receptor 3[14] and inhibits some histone deacetylases;[15] and3) niacin is an NAD+ precursor (seenicotinamide adenine dinucleotide) which when converted to NAD+ can alter over 500 enzymatic reactions that play key roles in regulatinginflammation,mitochondrion functions,autophagy, andapoptosis.[13] 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 onHca2gene knockout cells or animals (i.e., cells or animals that had theirHCa2 genes removed or inactivated) orgene knockdown cells or animals (i.e., cells or animals that had theirHCa2 genes ability to express HCA2 greatly reduced).[16] The studies reported here on HCA2 activators focus on those that included experiments inHca2 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 to1) inhibitlipolysis and2) inhibit inflammation and thereby suppress the development of certain diseases in which inflammation contributes to their development and/or severity.[13][17][18] These diseases include:atherosclerosis,[19]stroke,Alzheimer's disease,Parkinson's disease,multiple sclerosis, pathological pain (i.e. pain due to the abnormal activation ofneurons),[13]mastitis,[20]hepatitis due to heavy alcohol consumption,[21]inflammatory bowel diseases, cancer of thecolon,[22] and, possibly,psoriasis[23] and brain damage due to heavy alcohol consumption.[24]
HCA2 is commonly formed and regarded as ahomodimer, i.e. to be composed of two adjoined HCA2 proteins. However, aheterodimer composed of the HCA2 protein adjoined to the HCA3 protein has been detected in human embryonic kidneyHEK 293 cells. The humanHCAR2 andHCAR3 genes sit next to each other on chromosome 12 at position 24.31 and have an amino acidsequence homology greater than 95%. While there appears to be no significant difference in the responses triggered by activation of cells expressing the HCA2 homodimerversus the HCA2/HCA3 heterodimer proteins, more studies are needed to confirm this.[13] Furthermore:1) HCA2 and HCA1 are found in most mammalian species but HCA3 is found only in higher primates[5] and2) 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.[25] 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".[13]
HCA2 is expressed by:1) certain cells in theimmune system, e.g.,neutrophils,monocytes,macrophages,dermaldendritic cells,[18] andlymphocytes;[13]2) cells in thesmall intestine andcolonepithelum that face the intestinallumen;[26]3) the skin'sepithelial cells,keratinocytes, andLangerhans cells;[27]4)brown andwhite adipose tissue fat cells;[28]5) cells in themammary gland'sepithelium;[20]6)hepatocytes;7)multinucleatedosteoclasts in bone tissues;8) kidneypodocytes;[13] and9) cells in thenervous system, e.g.,microglia cells in the brain'scerebral cortex andhippocampus,[24] cells in the eye'sretinal pigment epithelium,[29][30] theastrocytes andneurons in the brain'srostral ventrolateral medulla, and theperipheral nervous system'sSchwann andsatellite glial cells.[13]
In addition to butyric acid, β-hydroxybutyric acid, and niacin, the following agents have been reported to activate HCA2:monomethyl fumarate,[27]dimethyl fumarate (dimethyl fumarate is aprodrug, i.e. it does not directly activate HCA2 but is rapidly converted in animal intestines to monomethyl fumarate[23][31]),[13][32]Acifran (Acifran also binds to HCA3 but with less affinity for it than for HCA3[25]),Acipimox,SCH 900271,[27] MK-6892,[33] MK-1903,[34] GSK256073,[35] and N2L.[36]
Lipolysis is themetabolic pathway in whichtriglycerides arehydrolyzed, i.e., enzymatically broken down, into their component freefatty acids andglycerol. The activation of this pathway leads fat cells to release the newly freed fatty acids into the circulation and thereby raisesserum 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 inHcar2gene knockout mice. Thus, HCA2 functions to inhibit lipolysis and lower serum fatty acid levels in mice.[37] Niacin likewise inhibits lipolysis to lower free fatty acidplasma levels in humans. Furthermore, the HCA2-activating drug, MK-1903, when taken orally by healthy volunteers inphase 1 and 2clinical 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 oftriglycerides and HDL-c] (i.e.,cholesterol-associatedHigh density lipoprotein) which are niacin's therapeutic targets for treating primaryhyperlipidemia andhypertriglyceridemia. These findings suggest but need further studies to determine if niacin and Mk-1903 inhibit lipolysis in humans by activating HCA2.[38] Studies suggest that HCA1 and, possibly, HCA3 also inhibit lipolysis.[27]
Atherosclerosis is a chronic inflammatoryarterial disease that can cause the narrowing or occlusion ofarteries and thereby variouscardiovascular diseases such asheart attacks andstrokes. In a murineApoE−/− model of atherosclerosis, mice were fed acholesterol‐rich (i.e., atherosclerosis-promoting) diet concurrently with β-hydroxybutyric acid, nicotine, or salt water daily for 9 weeks. Theaortas of β-hydroxybutyric acid-treated and niacin-treated mice had far lesshistological evidence of atherosclerosis (i.e., lessatherosclerotic plaques, lipid depositions, and infiltratingM1 inflammation-promotingmacrophages) than salt water-treated mice. β-Hydroxybutyric acid-fed mice also had significantly lower bloodplasma levels of three pro-inflammatory cytokines,tumor necrosis factor-α,interleukin-6, andinterleukin-1β, than salt water-treated mice. Further studies found that1) β-hydroxybutyric acid inhibitedlipopolysaccharide-simulated maturation of normalbone marrow‐derived macrophages to M1 macrophages but did not do so in macrophages taken from the bone marrows ofHcar2 gene knockout mice and2) mice constructed to haveHcar2 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.[13][39]
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.[13] 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 theirmiddle 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 inHca2 gene knockout mice. Niacin likewise reduced the size of the damaged brain site in normal but not inHca2 gene knockout mice. And, mice feed aketogenic 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-bearingmonocytes and/ormacrophages to produceprostaglandin D2.[40] (Prostaglandin D2 has anti-inflammatory actions.[41]) Finally, several other studies, while not examiningHcar2 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.[13]
Alzheimer's disease is a form ofdementia that is associated with the activation of the brain's pro-inflammatory microglial cells; the increased production of pro-inflammatorycytokines; and the accumulation in the brain ofa) extracellularamyloid plaques consisting ofmisfoldedamyloid-β protein,b)amyloid-beta precursor protein (which isenzymatically broken down to amyloid-β protein), andc) intracellular aggregates ofhyperphosphorylatedtau protein. Individuals with Alzheimer's disease commonly show progressively worsening declines incognitive, behavioral, and sensorimotor functions[42] along with increasing accumulations of aggregated amyloid-β proteins (which may be a key factor in the development of Alzheimer's disease).[43] In the 5XFAD murine model of Alzheimer's disease, mice were treated with β-hydroxybutyric acid or a placebo. Compared to placebo-treated mice, β-hydroxybutyric acid-mice showed better performances incognitive/memory testing; lower brain levels of the pro-inflammatory cytokinesinterleukin-1 beta,tumor necrosis factor-alpha, andinterleukin-6; lower levels of brain amyloid-beta precursor protein and amyloid-β protein; and higher levels ofneprilysin, an enzyme that degrades amyloid proteins and is essential to prevent Alzheimer's disease in mice (i.e., mice lacking a functional gene that encodes neprilysin develop Alzheimer's disease-like symptoms).[13][42] In another study, 5xFAD mice who received β-hydroxybutyric acid subcutaneously for 28 days showed better cognitive functions, lower levels of Aβ peptide accumulation in the brain, and greater activation of microglia cells in the brain compared to placebo-treated mice. Furthermore, HCA2 messenger RNA levels were increased in the brains of these mice during the period of active plaque deposition. (The postmortem brain tissues of patients with Alzheimer's disease also contained higher HCA2 messenger RNA levels that those of individuals who did not have Alzheimer's disease.)[42] In a third study, 5XFAD control mice that had normal levels of HCA2 or had theirHca2 gene knocked out were treated with a FDA-approved formulation of niacin, Niaspan. Niaspan-treated control mice had less brainneuron losses, fewer and smaller brain plaques, and better memory (as measured on a y-maze task test) than mice not treated with Niaspan: Niaspan did not produce these changes inHca2 gene knockout mice.[43] These results indicate that HCA2 suppresses the progression of Alzheimer's disease in a mouse model and support further studies with the ultimate goal of determining if HCA2 activators would be a useful addition to the treatment of Alzheimer's disease.[13][34][42][43]
Individuals with Parkinson's disease develop progressively less control of theirmotor movements in association with progressively greater losses ofdopamine neurons within thepars compacta subdivision of their brain'ssubstantia nigra. After longer times with the disease, individuals may also develop worseningcognition symptoms and, ultimately,Parkinson's disease dementia.[44] Some studies suggest that HCA2 may act to suppress this disease's progression. In a mouse model of Parkinson's disease, control male mice andHcar2 gene knockout male mice received lipopolysaccharide (an inflammation-inducingbacterial toxin) injections into the right substantia nigra of their brains and examined 28 days after the injections. Compared to control mice,Hcar2 gene knockout mice evidenced greater injury to their dopamine neurons, severer motor deficits, and more inflammation as judged by the levels of three pro-inflammatory cytokines (i.e., interleukin-6,interleukin-1β, and tumor necrosis factor-α) in their midbrain tissues andserum. Further studies examined mice that had theirHcar2 gene knocked out in their microglia but not in other tissues. Following the lipopolysaccharide injection protocol just described, the mice were feed a niacin solution for 28 days. This regimen alleviated dopamine neuron injuries and motor deficits in control mice but not in mice constructed to haveHcar2 gene knockout microglial cells.[45] In the model ofMPTP-induced Parkinson's disease, mice receivedintraperitoneal injections of MPTP or aplacebo (e.g., salt water) daily for 7 days followed by daily feeding (bygavage) of a salt water placebo, butyric acid, or monomethyl fumarate for 14 days. Compared to mice not treated with MPTP, mice treated with MPTP followed by salt water developed defective motor functions as defined in three different tests, lower dopamine levels in their corpus striatum, activation of the microglia in theirsubstantia nigra, and evidence of systemic inflammation (i.e., increased serum levels of the pro-inflammatory cytokines, tumor necrosis factor-α and interleuken-6). Mice treated with MPTP followed by butyric acid or monomethyl fumarate were significantly protected from developing these changes. Further studies suggested that the activation of HCA2 on microglial cells stimulated their change from a pro-inflammatory to anti-inflammatoryphenotype.[46] These results indicate that HCA2 suppresses the inflammation, neuronal damage, and neurological symptoms in mouse Parkinson's disease models and suggest that agents activating this receptor may be of use in treating and therefore should be further studied in humans with this disease.[13][45][46]
Multiple sclerosis is anautoimmunedemyelinating disease in which an individual's immune system's causes an inflammation-based destruction of themyelin sheath surroundingneurons in thecentral nervous system. This disrupts the afflicted neurons' functions and causes various neurological symptoms depending on which neurons are damaged.[13] In a murineexperimental autoimmune encephalomyelitis model of multiple sclerosis, mice taking oral dimethyl fumarate had less immune cell infiltration and demyelination in their spinal cords and improved motor function compared to mice not treated with dimethyl fumarate. These dimethyl fumarate-induced improvements did not occur inHcar2 gene knockout mice.[13][47] Studies in lipopolysaccaride-treatedcultured murine microglial cells found that monomethyl fumarate switched the cells from a pro-inflammatory to an anti-inflammatoryphenotype. Microglial cells pretreated with an antibody that binds to and thereby blocks activation of HCA2 did not show these phenotypic changes. These studies indicate that HCA2 acts to suppress the inflammation and thereby neurological symptoms in a mouse model of multiple sclerosis. In 2013, theFederal Drug Administration approved dimethyl fumarate (trade name Tecfidera[31]) for the treatment of multiple sclerosis.[5] Although it is now regarded as one of the front-line (i.e. first used) therapies for treating this disease, dimethyl fumarate'smechanism of action, including its impact on HCA2 in human multiple sclerosis, has not yet been defined[31] and needs further study.[13]
Pathologic pain is due to the abnormal activation of neurons inpain signaling pathways)[13][48] For example, neurons in thevertebral column'sposterior horn of thespinal cord are part of one pain signaling pathway. Excessive activation of these neurons caused by inflammation stimulates the production of pro-inflammatory cytokines (e.g., interleukin-2 and tumor necrosis factor-α) and persistentnociplastic pain.[48] Numerous studies in mice and rats have reported that β-hydroxybutyric acid, dimethyl fumarate, and MK-1903 haveanalgesic effects in models of thermal and mechanical hypersensitivity due to tibial bone fracture,intervertebral disc degeneration, complete Freund's adjuvant-induced arthritis,systemic lupus erythematosus, and chronic constriction of thesciatic nerve.[13] In the mouse model of pain induced by chronic constriction of the sciatic nerve, the pain-relieving effects of β-hydroxybutyric acid and dimethyl fumarate did not occur inHca2gene knockout mice.[49] These results indicate that HCA2 suppresses various types of pathological pain in mice and support studies to learn if it does so in humans.[13]
Mastitis is an infection-related or sterile inflammation of breast tissue. In a murine model ofmastitis, post-pregnant female mice drank niacin-containing or normal water for 26 days and then received lipopolysaccharide injections into the fourth pair of theirmammary glands. The next day each mammary gland was examined. Mouse fed pure water had extensive inflammation of their lipopolysaccharide-injected mammary glands, elevated mammary gland levels of pro-inflammatory cytokines (i.e., interleukin-6, interleukin-1β, and tumor necrosis factor-α), severe structural abnormalities such as thickened walls around their breasts' milk-producingalveoli, and breakdown of the blood-milk barrier which prevents uncontrolled exchange of components between the blood and alveolar milk. The mammary glands of lipopolysaccharide-injected, niacin-fed control mice but not niacin-fedHca2 gene knockout mice had far less of these changes. These results indicate that HCA2 functions to suppress the inflammation and tissue injuries that develop in a mouse model of mastitis.[20] HCA2 may play a similar role inbovines: dairy cows with mastitis that were fed niacin for 7 days showed decreases in their serum and milk levels of pro-inflammatory cytokines (i.e., tumor necrosis factor-α, interleukin-6, and interleukin-1β) and fewer cells in their milk compared to cows with mastitis that were not treated with niacin. It was also noted that the mammary tissue levels of HCA2 were higher in cows with than those without mastitis.[50] Thus, HCA2 may prove to be a target for treating mastitis in cows and might be useful to examine its roles in the in human mastitis.[20][50]
In a model ofalcohol-induced hepatitis, β-hydroxybutyric acid-treated mice showed less evidence of liver inflammation compared to control mice as indicated by their:1) lowerplasma levels ofalanine transaminase (an enzyme released into the bloodstream by damaged liver cells);2) less liversteatosis (i.e., lower levels of liver fat); and3) lower numbers of inflammation-promotingneutrophils, higher numbers of inflammation-suppressingM2 macrophages, and higher levels ofmessenger RNA encoding an inflammation-suppressing cytokine,IL-10, in their livers. The inflammation-reducing effects of β-hydroxybutyric acid did not occur inHcar2 gene knockout mice. In human studies, the concentration of β-hydroxybutyric acid in the livers of ten patients with alcoholic hepatitis was significantly lower than that of normal individuals. These findings indicate that HCA2 acts to reduce the severity of alcohol-induced hepatitis in mice and suggest that it may also do so, and therefore should be further studied, in humans.[21]
Inflammatory bowel diseases, i.e.,ulcerative colitis andCrohn's disease, are chronic inflammatory diseases of thegastrointestinal tract that can progress tocolon cancer.[22] Colon cancer, even if not preceded by an inflammatory bowel disease, commonly shows the presence of the inflammation response that is mounted to fight invading intestinalmicroorganisms. In a murine model of colitis, rats were given niacin or water for 2 weeks, given dailyrectal injections of the colitis-inducing agent,iodoacetamide, and sacrificed on day 15. Compared to water-treated rats, niacin-treated rats developed milder colitis as defined by less declines in body weight, less declines in colon weights, and less rises in colon tissue levels ofmyeloperoxidase, an indicator of inflammatory cell (i.e.polymorphonuclear leukocytes) infiltration. In a murine model of colitis leading to colon cancer, mice were treated with dextran sulfate sodium to produce colitis and an intraperitoneal injection ofazoxymethane, a colon cancer-causingcarcinogen. In this ApcMin/+ murine model:1) mice fed a diet that greatly reduced the levels of butyric acid in the colon developed colitis and numerous potentially pre-cancerous colonpolyps;2) mice fed a normal diet had less of these changes; and3) niacin treatment of mice fed the butyric acid-reducing diet suppressed these changes but did not do so inHcar2 gene knockout mice on the butyric acid-reducing diet.[22] Thus, HCA2 acts to inhibit colitis in rat as well as mouse models of colitis and in the mouse ulcerative colitis model reduced the formation of potentially pre-cancerous polyps.[22] In human studies, the levels ofmessenger RNA encoding HCA2 in 18 individuals with colon cancer were far lower in their cancers than their normal colon tissues and were also lower in 10 human colon cancercell lines than 2 human non-cancerous colon cell lines. (HCA3 messenger RNA levels were also lower in the colon cancer than non-cancerous colon tissue of the patients.) Furthermore, individuals who have inflammatory bowel disease and consume a diet that increases their levels of β-hydroxybutyric and butyric acid have been suggested to show clinical improvements in their disease and a reduced rate of it progressing to colon cancer.[26] These findings suggest that human colon cancers not preceded by an inflammatory bowel disease are associated with reductions in the expression of HCA2 (and HCA3) due togene silencing, that the reductions of HCA2 (and/or HCA3) may be involved in the development and/or progression of these cancers.[51][52] and that HCA2 may act to suppress human ulcerative colitis as well as its progression to colon cancer.[26]
Activators of HCA2 have been shown to suppress the inflammation and severity of disease in two other animal models. However, these studies did not examineHca2 gene knockout/knockdown animals. These models are forpsoriasis[23] and brain tissue inflammation, injury, and behavioral abnormalities caused byalcohol.[24]
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