Hydroxycarboxylic acid receptor 2

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. 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, 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; 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,), Acifran (Acifran also binds to HCA3 but with less affinity for it than for HCA3 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. (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. along with increasing accumulations of aggregated amyloid-β proteins (which may be a key factor in the development of Alzheimer's disease). 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 in cognitive/memory testing; lower brain levels of the pro-inflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6; lower levels of brain amyloid-beta precursor protein and amyloid-β protein; and higher levels of neprilysin, 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). Some studies suggest that HCA2 may act to suppress this disease's progression. In a mouse model of Parkinson's disease, control male mice and Hcar2 gene knockout male mice received lipopolysaccharide (an inflammation-inducing bacterial 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 and serum. Further studies examined mice that had their Hcar2 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 have Hcar2 gene knockout microglial cells. In the model of MPTP-induced Parkinson's disease, mice received intraperitoneal injections of MPTP or a placebo (e.g., salt water) daily for 7 days followed by daily feeding (by gavage) 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 their substantia 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-inflammatory phenotype. 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. Studies in lipopolysaccaride-treated cultured murine microglial cells found that monomethyl fumarate switched the cells from a pro-inflammatory to an anti-inflammatory phenotype. 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, the Federal Drug Administration approved dimethyl fumarate (trade name Tecfidera For example, neurons in the vertebral column's posterior horn of the spinal 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 persistent nociplastic pain. These results indicate that HCA2 suppresses various types of pathological pain in mice and support studies to learn if it does so in humans. 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. and that HCA2 may act to suppress human ulcerative colitis as well as its progression to colon cancer. Other diseases Activators of HCA2 have been shown to suppress the inflammation and severity of disease in two other animal models. However, these studies did not examine Hca2 gene knockout/knockdown animals. These models are for psoriasis and brain tissue inflammation, injury, and behavioral abnormalities caused by alcohol. ==Ligands==

;Agonists • GSK256073 • MK6892 == References ==