The mouse ortholog of NIACR1, Niacr1, has recently been proposed to mediate the ability of 5-oxo-ETE, a member of the 5-HETE family of eicosanoids, to stimulate the production of steroidogenic acute regulatory protein mRNA, Steroidogenic acute regulatory protein, and thereby progesterone in mouse cultured MA-10 Leydig cells. Human tissues respond to 5-oxo-ETE and other 5-HETE family members though the OXER1 G protein-coupled receptor. The roles, if any, of Niacr1 in the response of leydig cells to other 5-HETE family members, of Niacr1 in the response of other mouse cells to 5-HETE family members, and the role of NIACR1 in the response of human tissues to 5-HETE family members has not been determined.
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^Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S (Mar 2003). "PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect". Nature Medicine9 (3): 352–5. doi:10.1038/nm824. PMID12563315.
^ abcOffermanns S, Schwaninger M (2015). "Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation". Trends Mol Med21 (4): 245–255. doi:10.1016/j.molmed.2015.02.002. PMID25766751. Neuroinflammatory cells express HCA2, a receptor for the endogenous neuroprotective ketone body β-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation.
^Chai JT, Digby JE, Choudhury RP (May 2013). "GPR109A and vascular inflammation". Curr Atheroscler Rep15 (5): 325. doi:10.1007/s11883-013-0325-9. PMC3631117. PMID23526298. This interest is generated especially because of the continuing exploration of niacin's "pleiotropic" mechanisms of action and its potential in the "cross-talk" between metabolic and inflammatory pathways. As GPR109A's primary pharmacological ligand in clinical use, niacin has been used for over 50 years in the treatment of cardiovascular disease, mainly due to its favourable effects on plasma lipoproteins. However, it has become apparent that niacin also possesses lipoprotein-independent effects that influence inflammatory pathways mediated through GPR109A. In addition to its G-protein-mediated effects, recent evidence has emerged to support alternative GPR109A signalling via adaptive protein β-arrestins.
^Graff EC, Fang H, Wanders D, Judd RL (February 2016). "Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2". Metab. Clin. Exp.65 (2): 102–113. doi:10.1016/j.metabol.2015.10.001. PMID26773933. HCA2 is highly expressed on immune cells, including macrophages, monocytes, neutrophils and dermal dendritic cells, among other cell types. ... Recent studies demonstrate that HCA2 mediates profound anti-inflammatory effects in a variety of tissues, indicating that HCA2 may be an important therapeutic target for treating inflammatory disease processes.
^ abWakade C, Chong R (December 2014). "A novel treatment target for Parkinson's disease". J. Neurol. Sci.347 (1-2): 34–38. doi:10.1016/j.jns.2014.10.024. PMID25455298. GPR109A and its agonists are known to exert anti-inflammatory actions in the skin, gut and retina.
^Zhang Y, Schmidt RJ, Foxworthy P, Emkey R, Oler JK, Large TH, Wang H, Su EW, Mosior MK, Eacho PI, Cao G (Aug 2005). "Niacin mediates lipolysis in adipose tissue through its G-protein coupled receptor HM74A". Biochemical and Biophysical Research Communications334 (2): 729–32. doi:10.1016/j.bbrc.2005.06.141. PMID16018973.
^Tang Y, Zhou L, Gunnet JW, Wines PG, Cryan EV, Demarest KT (Jun 2006). "Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A". Biochemical and Biophysical Research Communications345 (1): 29–37. doi:10.1016/j.bbrc.2006.04.051. PMID16674924.
^Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I (2015). "Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation". Nutrients7 (4): 2839–49. doi:10.3390/nu7042839. PMC4425176. PMID25875123. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues.
^Hoeppli RE, Wu D, Cook L, Levings MK (February 2015). "The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome". Front Immunol6: 61. doi:10.3389/fimmu.2015.00061. PMC4332351. PMID25741338. Specific species that have been recognized by their high levels of butyrate production include Faecalibacterium prausnitzii and the cluster IV and XIVa of genus Clostridium ... Administration of acetate, propionate, and butyrate in drinking water mimics the effect of Clostridium colonization in germ-free mice, resulting in an elevated Treg frequency in the colonic lamina propria and increased IL-10 production by these Tregs (180, 182). Of the three main SCFAs, butyrate has been found to be the most potent inducer of colonic Tregs. Mice fed a diet enriched in butyrylated starches have more colonic Tregs than those fed a diet containing propinylated or acetylated starches (181). Arpaia et al. tested an array of SCFAs purified from commensal bacteria and confirmed butyrate was the strongest SCFA-inducer of Tregs in vitro (180). Mechanistically, it has been proposed that butyrate, and possibly propionate, promote Tregs through inhibiting histone deacetylase (HDAC), causing increased acetylation of histone H3 in the Foxp3 CNS1 region, and thereby enhancing FOXP3 expression (180, 181). Short-chain fatty acids partially mediate their effects through G-protein coupled receptors (GPR), including GPR41, GPR43, and GPR109A. GPR41 and GPR43 are stimulated by all three major SCFAs (191), whereas GPR109A only interacts with butyrate (192). Figure 1: Microbial-derived molecules promote colonic Treg differentiation.