The hydroxycarboxylic acid family of receptors (ENSFM00500000271913, nomenclature as agreed by the NC-IUPHAR Subcommittee on Hydroxycarboxylic acid receptors [5,8]) respond to organic acids, including the endogenous hydroxy carboxylic acids 3-hydroxy butyric acid and L-lactic acid, as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran [15,20-21]. These receptors were provisionally described as nicotinic acid receptors, although nicotinic acid shows submicromolar potency at HCA₂ receptors only and is unlikely to be the natural ligand [20-21].

Further closely-related GPCRs include the 5-oxoeicosanoid receptor (OXER1, Q8TDS5) and GPR31 (O00270). Lactate activates HCA₁ on adipocytes in an autocrine manner. It inhibits lipolysis and thereby promotes anabolic effects. HCA₂ and HCA₃ regulate adipocyte lipolysis and immune functions under conditions of increased FFA formation through lipolysis (e.g., during fasting). HCA₂ agonists acting mainly through the receptor on immune cells exert antiatherogenic and anti-inflammatory effects. HCA₂ is also a receptor for butyrate and mediates some of the beneficial effects of short-chain fatty acids produced by gut microbiota. HCA₃ has been shown to be activated by aromatic D-amino acids, and by D-phenyllactic acid, a metabolite of gut lactic acid bacteria [10].

* Key recommended reading is highlighted with an asterisk

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* Graff EC, Fang H, Wanders D, Judd RL. (2016) Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metab Clin Exp, 65 (2): 102-13. [PMID:26773933]

Hanson J, Gille A, Offermanns S. (2012) Role of HCA₂ (GPR109A) in nicotinic acid and fumaric acid ester-induced effects on the skin. Pharmacol Ther, 136 (1): 1-7. [PMID:22743741]

* Kamanna VS, Ganji SH, Kashyap ML. (2013) Recent advances in niacin and lipid metabolism. Curr Opin Lipidol, 24 (3): 239-45. [PMID:23619367]

* Kennedy L, Glesaaen ER, Palibrk V, Pannone M, Wang W, Al-Jabri A, Suganthan R, Meyer N, Austbø ML, Lin X et al.. (2022) Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia. Elife, 11. DOI: 10.7554/eLife.76451 [PMID:35942676]

Offermanns S. (2014) Free fatty acid (FFA) and hydroxy carboxylic acid (HCA) receptors. Annu Rev Pharmacol Toxicol, 54: 407-34. [PMID:24160702]

* Offermanns S. (2017) Hydroxy-Carboxylic Acid Receptor Actions in Metabolism. Trends Endocrinol Metab, 28 (3): 227-236. [PMID:28087125]

* Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP. (2011) International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B). Pharmacol Rev, 63 (2): 269-90. [PMID:21454438]

* Offermanns S, Schwaninger M. (2015) Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation. Trends Mol Med, 21 (4): 245-55. [PMID:25766751]

Soudijn W, van Wijngaarden I, Ijzerman AP. (2007) Nicotinic acid receptor subtypes and their ligands. Med Res Rev, 27 (3): 417-33. [PMID:17238156]

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Subcommittee members: Stefan Offermanns (Chairperson) Professor of Pharmacology Director Max-Planck-Institute for Heart and Lung Research Ludwigstraße 43 61231 Bad Nauheim Germany and Medical Faculty Goethe-University Frankfurt Theodor-Stern-Kai 7 60590 Frankfurt am Main Germany Steven L. Colletti Department of Medicinal Chemistry Merck Research Laboratories Merck & Co., Inc. West Point Pennsylvania 19486 USA Adriaan P. IJzerman Professor of Medicinal Chemistry Leiden-Amsterdam Centre for Drug Research Gorlaeus Laboratories, Leiden University PO Box 9502 Leiden, 2300 RA, The Netherlands Timothy W. Lovenberg Janssen Research & Development LLC 3210 Merryfield Row San Diego California, 92109 USA Graeme Semple Beacon Discovery Inc 6118 Nancy Ridge Dr. San Diego CA 92121 USA Alan Wise 7TMR Systems Research GlaxoSmithKline Medicines Research Centre Gunnels Wood Rd. Stevenage Hertfordshire SG1 2NY UK

Other contributors: M. Gerard Waters Dept. of Cardiovascular Diseases Merck Research Laboratories 126 E. Lincoln Ave. Rahway NJ 07065 USA