Free fatty acid receptor

{{Short description|G-protein coupled receptor which binds free fatty acids}}

{{infobox protein

| Name = free fatty acid receptor 1

| caption =

| image =

| width =

| HGNCid = 4498

| Symbol = FFAR1, FFA1R

| AltSymbols = GPR40

| EntrezGene = 2864

| OMIM = 603820

| RefSeq = NM_005303

| UniProt = O14842

| PDB =

| ECnumber =

| Chromosome = 19

| Arm = q

| Band = 13.1

| LocusSupplementaryData =

}}

{{infobox protein

| Name = free fatty acid receptor 2

| caption =

| image =

| width =

| HGNCid = 4501

| Symbol = FFAR2

| AltSymbols = GPR43, FFA2R

| EntrezGene = 2867

| OMIM = 603823

| RefSeq = NM_005306

| UniProt = O15552

| PDB =

| ECnumber =

| Chromosome = 19

| Arm = q

| Band = 13.1

| LocusSupplementaryData =

}}

{{infobox protein

| Name = free fatty acid receptor 3

| caption =

| image =

| width =

| HGNCid = 4499

| Symbol = FFAR3

| AltSymbols = GPR41, FFA3R

| EntrezGene = 2865

| OMIM = 603821

| RefSeq = NM_005304

| UniProt = O14843

| PDB =

| ECnumber =

| Chromosome = 19

| Arm = q

| Band = 13.1

| LocusSupplementaryData =

}}

{{Infobox protein

| name = free fatty acid receptor 4

| AltNames =

| image =

| width =

| caption =

| Symbol = FFAR4

| AltSymbols = BMIQ10, GPR120, GPR129, GT01, O3FAR1, PGR4, free fatty acid receptor 4

| IUPHAR_id =

| ATC_prefix =

| ATC_suffix =

| ATC_supplemental =

| CAS_number =

| CAS_supplemental =

| DrugBank =

| EntrezGene = 338557

| HGNCid =

| OMIM = 609044

| PDB =

| RefSeq = NM_181745

| UniProt = Q5NUL3

| ECnumber =

| Chromosome = 10

| Arm = q

| Band = 23.33

| LocusSupplementaryData =

| Wikidata =

}}

{{infobox protein

| Name = G protein-coupled receptor 42

| caption =

| image =

| width =

| HGNCid = 4500

| Symbol = GPR42

| AltSymbols = GPR41L, FFAR1L

| EntrezGene = 2866

| OMIM = 603822

| RefSeq = NM_005305

| UniProt = O15529

| PDB =

| ECnumber =

| Chromosome = 19

| Arm = q

| Band = 31.1

| LocusSupplementaryData =

}}

Free fatty acid receptors (FFARs) are G-protein coupled receptors (GPRs).{{cite journal | vauthors = Covington DK, Briscoe CA, Brown AJ, Jayawickreme CK | title = The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensing | journal = Biochem. Soc. Trans. | volume = 34 | issue = Pt 5 | pages = 770–3 | year = 2006 | pmid = 17052194 | doi = 10.1042/BST0340770 }} GPRs (also termed seven-(pass)-transmembrane domain receptors) are a large family of receptors. They reside on their parent cells' surface membranes, bind any one of a specific set of ligands that they recognize, and thereby are activated to elicit certain types of responses in their parent cells.{{cite journal | vauthors = Weis WI, Kobilka BK | title = The Molecular Basis of G Protein-Coupled Receptor Activation | journal = Annual Review of Biochemistry | volume = 87 | issue = | pages = 897–919 | date = June 2018 | pmid = 29925258 | pmc = 6535337 | doi = 10.1146/annurev-biochem-060614-033910 | url = }} Humans express more than 800 different types of GPCRs.{{cite journal | vauthors = Liang C, Li J, Tian B, Tian L, Liu Y, Li J, Xin L, Wang J, Fu C, Shi Z, Xia J, Liang Y, Wang K | title = Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment | journal = Biomedicine & Pharmacotherapy | volume = 144 | issue = | pages = 112298 | date = December 2021 | pmid = 34649219 | doi = 10.1016/j.biopha.2021.112298 | s2cid = 238990829 | url = | doi-access = free }} FFARs are GPCR that bind and thereby become activated by particular fatty acids. In general, these binding/activating fatty acids are straight-chain fatty acids consisting of a carboxylic acid residue, i.e., -COOH, attached to aliphatic chains, i.e. carbon atom chains of varying lengths with each carbon being bound to 1, 2 or 3 hydrogens (CH1, CH2, or CH3).{{cite journal | vauthors = Karmokar PF, Moniri NH | title = Oncogenic signaling of the free-fatty acid receptors FFA1 and FFA4 in human breast carcinoma cells | journal = Biochemical Pharmacology | volume = 206 | issue = | pages = 115328 | date = December 2022 | pmid = 36309079 | doi = 10.1016/j.bcp.2022.115328 | s2cid = 253174629 | url = }} For example, propionic acid is a short-chain fatty acid consisting of 3 carbons (C's), CH3-CH2-COOH, and docosahexaenoic acid is a very long-chain polyunsaturated fatty acid consisting of 22 C's and six double 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.{{cite journal | vauthors = Secor JD, Fligor SC, Tsikis ST, Yu LJ, Puder M | title = Free Fatty Acid Receptors as Mediators and Therapeutic Targets in Liver Disease | journal = Frontiers in Physiology | volume = 12 | issue = | pages = 656441 | date = 2021 | pmid = 33897464 | pmc = 8058363 | doi = 10.3389/fphys.2021.656441 | url = | doi-access = free }}

Currently, four FFARs are recognized: FFAR1, also termed GPR40; FFAR2, also termed GPR43; FFAR3, also termed GPR41; and FFAR4, also termed GPR120.{{cite journal | vauthors = Frei R, Nordlohne J, Hüser U, Hild S, Schmidt J, Eitner F, Grundmann M | title = Allosteric targeting of the FFA2 receptor (GPR43) restores responsiveness of desensitized human neutrophils | journal = Journal of Leukocyte Biology | volume = 109 | issue = 4 | pages = 741–751 | date = April 2021 | pmid = 32803826 | pmc = 8048482 | doi = 10.1002/JLB.2A0720-432R | url = }} The human FFAR1, FFAR2, and FFAR3 genes are located close to each other on the long (i.e., "q") arm of chromosome 19 at position 23.33 (notated as 19q23.33). This location also includes the GPR42 gene (previously termed the FFAR1L, FFAR3L, GPR41L, and GPR42P gene). This gene appears to be a segmental duplication of the FFAR3 gene. The human GPR42 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.{{cite journal | vauthors = Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ | title = The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids | journal = The Journal of Biological Chemistry | volume = 278 | issue = 13 | pages = 11312–9 | date = March 2003 | pmid = 12496283 | doi = 10.1074/jbc.M211609200 | url = | doi-access = free }}{{cite journal | vauthors = Liaw CW, Connolly DT | title = Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42 | journal = DNA and Cell Biology | volume = 28 | issue = 11 | pages = 555–60 | date = November 2009 | pmid = 19630535 | doi = 10.1089/dna.2009.0916 | url = }}{{cite journal | vauthors = Puhl HL, Won YJ, Lu VB, Ikeda SR | title = Human GPR42 is a transcribed multisite variant that exhibits copy number polymorphism and is functional when heterologously expressed | journal = Scientific Reports | volume = 5 | issue = | pages = 12880 | date = August 2015 | pmid = 26260360 | pmc = 4531286 | doi = 10.1038/srep12880 | bibcode = 2015NatSR...512880P | url = }}{{cite journal | vauthors = Pluznick JL | title = Microbial Short-Chain Fatty Acids and Blood Pressure Regulation | journal = Current Hypertension Reports | volume = 19 | issue = 4 | pages = 25 | date = April 2017 | pmid = 28315048 | pmc = 5584783 | doi = 10.1007/s11906-017-0722-5 | url = }} The human FFAR1 gene is located on the long (i.e. "q") arm of chromosome 10 (notated as 10q23.33).{{cite journal | vauthors = 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 | title = Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human | journal = Nature | volume = 483 | issue = 7389 | pages = 350–4 | date = February 2012 | pmid = 22343897 | doi = 10.1038/nature10798 | bibcode = 2012Natur.483..350I | url = | hdl = 2433/153278 | s2cid = 4427480 | hdl-access = free }}

FFAR2 and FFAR3 bind and are activated by short-chain fatty acids, i.e., fatty acid chains consisting of 6 or less carbon atoms such as acetic, butyric, proprionic, pentanoic, and hexanoic acids.{{cite journal | vauthors = Ang Z, Xiong D, Wu M, Ding JL | title = FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing | journal = FASEB Journal | volume = 32 | issue = 1 | pages = 289–303 | date = January 2018 | pmid = 28883043 | pmc = 5731126 | doi = 10.1096/fj.201700252RR | doi-access = free | url = }}{{cite journal | vauthors = Kimura I, Ichimura A, Ohue-Kitano R, Igarashi M | title = Free Fatty Acid Receptors in Health and Disease | journal = Physiological Reviews | volume = 100 | issue = 1 | pages = 171–210 | date = January 2020 | pmid = 31487233 | doi = 10.1152/physrev.00041.2018 | url = | doi-access = free }} β-hydroxybutyric acid has been reported to stimulate or inhibit FFAR3.{{cite journal | vauthors = Won YJ, Lu VB, Puhl HL, Ikeda SR | title = β-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3 | journal = The Journal of Neuroscience | volume = 33 | issue = 49 | pages = 19314–25 | date = December 2013 | pmid = 24305827 | pmc = 3850046 | doi = 10.1523/JNEUROSCI.3102-13.2013 | url = }} FFAR1 and FFAR4 bind to and are activated by medium-chain fatty acids (i.e., fatty acids consisting of 6-12 carbon atoms) such as lauric and capric acids{{cite journal | vauthors = Christiansen E, Hudson BD, Hansen AH, Milligan G, Ulven T | title = Development and Characterization of a Potent Free Fatty Acid Receptor 1 (FFA1) Fluorescent Tracer | journal = Journal of Medicinal Chemistry | volume = 59 | issue = 10 | pages = 4849–58 | date = May 2016 | pmid = 27074625 | doi = 10.1021/acs.jmedchem.6b00202 | url = https://eprints.gla.ac.uk/118427/11/118427.pdf}} and long-chain or very long-chain fatty acids (i.e., fatty acids consisting respectively of 13 to 21 or more than 21 carbon atoms) such as myristic, steric, oleic, palmitic, palmitoleic, linoleic, alpha-linolenic, dihomo-gamma-linolenic, eicosatrienoic, arachidonic (also termed eicosatetraenoic acid), eicosapentaenoic, docosatetraenoic, docosahexaenoic,{{cite journal | vauthors = Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR, Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S, Muir AI | title = The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids | journal = The Journal of Biological Chemistry | volume = 278 | issue = 13 | pages = 11303–11 | date = March 2003 | pmid = 12496284 | doi = 10.1074/jbc.M211495200 | url = | doi-access = free }} and 20-hydroxyeicosatetraenoic acids.{{cite journal | vauthors = Tunaru S, Bonnavion R, Brandenburger I, Preussner J, Thomas D, Scholich K, Offermanns S | title = 20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1 | journal = Nature Communications | volume = 9 | issue = 1 | pages = 177 | date = January 2018 | pmid = 29330456 | pmc = 5766607 | doi = 10.1038/s41467-017-02539-4 | bibcode = 2018NatCo...9..177T | url = }} Among the fatty acids that activate FFAR1 and FFAR4, docosahexaenoic and eicosapentaenoic acids are regarded as the main fatty acids that do so.{{cite journal | vauthors = Duah M, Zhang K, Liang Y, Ayarick VA, Xu K, Pan B | title = Immune regulation of poly unsaturated fatty acids and free fatty acid receptor 4 | journal = The Journal of Nutritional Biochemistry | volume = 112 | issue = | pages = 109222 | date = February 2023 | pmid = 36402250 | doi = 10.1016/j.jnutbio.2022.109222 | s2cid = 253652038 | url = }}

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 the knockout (i.e., total removal or inactivation) or knockdown (i.e., significant depression ) of the gene's GPR protein that mediates the fatty acid's action.{{cite journal | vauthors = Shimizu H, Masujima Y, Ushiroda C, Mizushima R, Taira S, Ohue-Kitano R, Kimura I | title = Dietary short-chain fatty acid intake improves the hepatic metabolic condition via FFAR3 | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 16574 | date = November 2019 | pmid = 31719611 | pmc = 6851370 | doi = 10.1038/s41598-019-53242-x | bibcode = 2019NatSR...916574S | url = }}{{cite journal | vauthors = Kim MJ, Kim JY, Shin JH, Kang Y, Lee JS, Son J, Jeong SK, Kim D, Kim DH, Chun E, Lee KY | title = FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB | journal = Cell & Bioscience | volume = 13 | issue = 1 | pages = 102 | date = June 2023 | pmid = 37287005 | pmc = 10249240 | doi = 10.1186/s13578-023-01038-y | url = | doi-access = free }}