Free fatty acid receptors (FFARs) areG-protein coupled receptors (GPRs).[1] GPRs (also termed seven-(pass)-transmembrane domain receptors) are a largefamily ofreceptors. They reside on their parent cells' surfacemembranes, bind any one of a specific set ofligands that they recognize, and thereby are activated to elicit certain types of responses in their parent cells.[2] Humans express more than 800 different types of GPCRs.[3] FFARs are GPCR that bind and thereby become activated by particularfatty acids. In general, these binding/activating fatty acids arestraight-chain fatty acids consisting of acarboxylic acid residue, i.e., -COOH, attached toaliphatic chains, i.e.carbon atom chains of varying lengths with each carbon being bound to 1, 2 or 3hydrogens (CH1, CH2, or CH3).[4] For example,propionic acid is ashort-chain fatty acid consisting of 3 carbons (C's), CH3-CH2-COOH, anddocosahexaenoic acid is a very long-chainpolyunsaturated fatty acid consisting of 22 C's and sixdouble bonds (double bonds notated as "="): CH3-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH1=CH1-CH2-CH2-COOH.[5]
Currently, four FFARs are recognized:FFAR1, also termed GPR40;FFAR2, also termed GPR43;FFAR3, also termed GPR41; andFFAR4, also termed GPR120.[6] The humanFFAR1, FFAR2, andFFAR3 genes are located close to each other on thelong (i.e., "q") arm ofchromosome 19 at position 23.33 (notated as 19q23.33). This location also includes theGPR42 gene (previously termed theFFAR1L, FFAR3L, GPR41L, and GPR42P gene). This gene appears to be asegmental duplication of theFFAR3 gene. The humanGPR42 gene codes for several proteins with a FFAR3-like structure but their expression in various cell types and tissues as well as their activities and functions have not yet been clearly defined. Consequently, none of these proteins are classified as an FFAR.[7][8][9][10] The humanFFAR1 gene is located on the long (i.e. "q") arm ofchromosome 10 (notated as 10q23.33).[11]
Many of the FFAR-activating fatty acids also activate other types of GPRs. The actual GPR activated by a fatty acid must be identified in order to understand its and the activated GPR's function. The following section gives the non-FFAR GPRs that are activated by FFAR-activating fatty acids. One of the most often used and best way of showing that a fatty acid's action is due to a specific GPR is to show that the fatty acid's action is either absent or significantly reduced in cells, tissues, or animals that have no or significantly reduced activity due, respectively, to theknockout (i.e., total removal or inactivation) orknockdown (i.e., significant depression ) of the gene's GPR protein that mediates the fatty acid's action.[13][19][20]
Other GPRs activated by FFAR-activating fatty acids
GPR84 binds and is activated by medium-chain fatty acids consisting of 9 to 14 carbon atoms such ascapric,undecaenoic, andlauric acids.[21][22] It has been recognized as a possible member of the free fatty acid receptor family in some publications[23] but has not yet been given this designation perhaps because these medium-chain fatty acid activators require very high concentrations (e.g., in the micromolar range) to activate it. This allows that there may be a naturally occurring agent(s) that activates GPR84 at lower concentrations than the cited fatty acids.[24] Consequently, GPR89 remains classified as anorphan receptor, i.e., a receptor who's naturally occurring activator(s) is unclear.[22]
GPR109A is also termed hydroxycarboxylic acid receptor 2,niacin receptor 1, HM74a, HM74b, and PUMA-G.[25] GPR109A binds and thereby is activated by the short-chain fatty acids, butyric,β-hydroxybutyric,[26][27]pentanoic andhexanoic acids and by the intermediate-chain fatty acidsheptanoic andoctanoic acids.[28] GPR109A is also activated by niacin but only at levels that are in general too low to activate it unless it is given as a drug in high doses.[26][29]
GPR81 (also termed hydroxycarboxylic acid receptor 1, HCAR1, GPR104, GPR81, LACR1, TA-GPCR, TAGPCR, and FKSG80) binds and is activated by the short-chain fatty acids,lactic acid[30][31] and β-hydroxybutyric acid.[32] A more recent study reported that it is also activated by the compound3,5-dihydroxybenzoic acid.[33]
GPR109B (also known as hydroxycarboxylic acid receptor 3, HCA3, niacin receptor 2, and NIACR2) binds and is activated by the medium-chain fatty acid, 3-hydroxyoctanoate,[34] niacin,[35] and by four compoundsviz., hippuric acid,[35] 4-hydroxyphenyllactic acid, phenyllacetic acid, and indole-3-lactic acid.[36] The latter three compounds are produced byLactobacillus andBifidobacterium species ofbacteria that occupy thegastrointestinal tracts of animals and humans.[36]
^Covington DK, Briscoe CA, Brown AJ, Jayawickreme CK (2006). "The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensing".Biochem. Soc. Trans.34 (Pt 5):770–3.doi:10.1042/BST0340770.PMID17052194.
^abKarmokar PF, Moniri NH (December 2022). "Oncogenic signaling of the free-fatty acid receptors FFA1 and FFA4 in human breast carcinoma cells".Biochemical Pharmacology.206 115328.doi:10.1016/j.bcp.2022.115328.PMID36309079.S2CID253174629.
^Liaw CW, Connolly DT (November 2009). "Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42".DNA and Cell Biology.28 (11):555–60.doi:10.1089/dna.2009.0916.PMID19630535.
^Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K, Choquet H, Besnard P, Lecoeur C, Vivequin S, Ayukawa K, Takeuchi M, Ozawa K, Tauber M, Maffeis C, Morandi A, Buzzetti R, Elliott P, Pouta A, Jarvelin MR, Körner A, Kiess W, Pigeyre M, Caiazzo R, Van Hul W, Van Gaal L, Horber F, Balkau B, Lévy-Marchal C, Rouskas K, Kouvatsi A, Hebebrand J, Hinney A, Scherag A, Pattou F, Meyre D, Koshimizu TA, Wolowczuk I, Tsujimoto G, Froguel P (February 2012). "Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human".Nature.483 (7389):350–4.Bibcode:2012Natur.483..350I.doi:10.1038/nature10798.hdl:2433/153278.PMID22343897.S2CID4427480.
^Duah M, Zhang K, Liang Y, Ayarick VA, Xu K, Pan B (February 2023). "Immune regulation of poly unsaturated fatty acids and free fatty acid receptor 4".The Journal of Nutritional Biochemistry.112 109222.doi:10.1016/j.jnutbio.2022.109222.PMID36402250.S2CID253652038.
^Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, Hiyama H, Matsuo A, Matsushime H, Furuichi K (March 2003). "Molecular identification of nicotinic acid receptor".Biochemical and Biophysical Research Communications.303 (1):364–9.doi:10.1016/s0006-291x(03)00342-5.PMID12646212.
^Cai TQ, Ren N, Jin L, Cheng K, Kash S, Chen R, Wright SD, Taggart AK, Waters MG (December 2008). "Role of GPR81 in lactate-mediated reduction of adipose lipolysis".Biochemical and Biophysical Research Communications.377 (3):987–91.doi:10.1016/j.bbrc.2008.10.088.PMID18952058.
^Wagner W, Sobierajska K, Pułaski Ł, Stasiak A, Ciszewski WM (April 2023). "Whole grain metabolite 3,5-dihydroxybenzoic acid is a beneficial nutritional molecule with the feature of a double-edged sword in human health: a critical review and dietary considerations".Critical Reviews in Food Science and Nutrition.64 (24):8786–8804.doi:10.1080/10408398.2023.2203762.PMID37096487.S2CID258310985.
"Free Fatty Acid Receptors".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2016-03-03. Retrieved2007-10-25.
