Biology:Free fatty acid receptor

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Short description: G-protein coupled receptor which binds free fatty acids
free fatty acid receptor 1
Identifiers
SymbolFFAR1, FFA1R
Alt. symbolsGPR40
NCBI gene2864
HGNC4498
OMIM603820
RefSeqNM_005303
UniProtO14842
Other data
LocusChr. 19 q13.1
free fatty acid receptor 2
Identifiers
SymbolFFAR2
Alt. symbolsGPR43, FFA2R
NCBI gene2867
HGNC4501
OMIM603823
RefSeqNM_005306
UniProtO15552
Other data
LocusChr. 19 q13.1
free fatty acid receptor 3
Identifiers
SymbolFFAR3
Alt. symbolsGPR41, FFA3R
NCBI gene2865
HGNC4499
OMIM603821
RefSeqNM_005304
UniProtO14843
Other data
LocusChr. 19 q13.1
free fatty acid receptor 4
Identifiers
SymbolFFAR4
Alt. symbolsBMIQ10, GPR120, GPR129, GT01, O3FAR1, PGR4, free fatty acid receptor 4
NCBI gene338557
OMIM609044
RefSeqNM_181745
UniProtQ5NUL3
Other data
LocusChr. 10 q23.33
G protein-coupled receptor 42
Identifiers
SymbolGPR42
Alt. symbolsGPR41L, FFAR1L
NCBI gene2866
HGNC4500
OMIM603822
RefSeqNM_005305
UniProtO15529
Other data
LocusChr. 19 q31.1

Free fatty acid receptors (FFARs) are G-protein coupled receptors (GPRs).[1] 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.[2] Humans express more than 800 different types of GPCRs.[3] 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).[4] 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.[5]

Currently, four FFARs are recognized: FFAR1, also termed GPR40; FFAR2, also termed GPR43; FFAR3, also termed GPR41; and FFAR4, also termed GPR120.[6] 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.[7][8][9][10] The human FFAR1 gene is located on the long (i.e. "q") arm of chromosome 10 (notated as 10q23.33).[11]

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.[7][12][13] β-hydroxybutyric acid has been reported to stimulate or inhibit FFAR3.[14] 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[15] 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,[4][13][16] and 20-hydroxyeicosatetraenoic acids.[17] Among the fatty acids that activate FFAR1 and FFAR4, docosahexaenoic and eicosapentaenoic acids are regarded as the main fatty acids that do so.[18]

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.[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 as capric, undecaenoic, and lauric 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 an orphan 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 and hexanoic acids and by the intermediate-chain fatty acids heptanoic and octanoic 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 compound 3,5-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 compounds viz., hippuric acid,[35] 4-hydroxyphenyllactic acid, phenyllacetic acid, and indole-3-lactic acid.[36] The latter three compounds are produced by Lactobacillus and Bifidobacterium species of bacteria that occupy the gastrointestinal tracts of animals and humans.[36]

GPR91 (also termed the succinic acid receptor, succinate receptor, or SUCNR1) is activated most potently by the short-chain dicarobxylic fatty acid, succinic acid; the short-chain fatty acids, oxaloacetic, malic, and α-ketoglutaric acids are less potent activators of GPR91.[37]

References

  1. ↑ "The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensing". Biochem. Soc. Trans. 34 (Pt 5): 770–3. 2006. doi:10.1042/BST0340770. PMID 17052194. 
  2. ↑ "The Molecular Basis of G Protein-Coupled Receptor Activation". Annual Review of Biochemistry 87: 897–919. June 2018. doi:10.1146/annurev-biochem-060614-033910. PMID 29925258. 
  3. ↑ "Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment". Biomedicine & Pharmacotherapy 144: 112298. December 2021. doi:10.1016/j.biopha.2021.112298. PMID 34649219. 
  4. ↑ 4.0 4.1 "Oncogenic signaling of the free-fatty acid receptors FFA1 and FFA4 in human breast carcinoma cells". Biochemical Pharmacology 206: 115328. December 2022. doi:10.1016/j.bcp.2022.115328. PMID 36309079. 
  5. ↑ "Free Fatty Acid Receptors as Mediators and Therapeutic Targets in Liver Disease". Frontiers in Physiology 12: 656441. 2021. doi:10.3389/fphys.2021.656441. PMID 33897464. 
  6. ↑ "Allosteric targeting of the FFA2 receptor (GPR43) restores responsiveness of desensitized human neutrophils". Journal of Leukocyte Biology 109 (4): 741–751. April 2021. doi:10.1002/JLB.2A0720-432R. PMID 32803826. 
  7. ↑ 7.0 7.1 "The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids". The Journal of Biological Chemistry 278 (13): 11312–9. March 2003. doi:10.1074/jbc.M211609200. PMID 12496283. 
  8. ↑ "Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42". DNA and Cell Biology 28 (11): 555–60. November 2009. doi:10.1089/dna.2009.0916. PMID 19630535. 
  9. ↑ "Human GPR42 is a transcribed multisite variant that exhibits copy number polymorphism and is functional when heterologously expressed". Scientific Reports 5: 12880. August 2015. doi:10.1038/srep12880. PMID 26260360. Bibcode: 2015NatSR...512880P. 
  10. ↑ "Microbial Short-Chain Fatty Acids and Blood Pressure Regulation". Current Hypertension Reports 19 (4): 25. April 2017. doi:10.1007/s11906-017-0722-5. PMID 28315048. 
  11. ↑ "Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human". Nature 483 (7389): 350–4. February 2012. doi:10.1038/nature10798. PMID 22343897. Bibcode: 2012Natur.483..350I. 
  12. ↑ "FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing". FASEB Journal 32 (1): 289–303. January 2018. doi:10.1096/fj.201700252RR. PMID 28883043. 
  13. ↑ 13.0 13.1 13.2 "Free Fatty Acid Receptors in Health and Disease". Physiological Reviews 100 (1): 171–210. January 2020. doi:10.1152/physrev.00041.2018. PMID 31487233. 
  14. ↑ "β-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3". The Journal of Neuroscience 33 (49): 19314–25. December 2013. doi:10.1523/JNEUROSCI.3102-13.2013. PMID 24305827. 
  15. ↑ "Development and Characterization of a Potent Free Fatty Acid Receptor 1 (FFA1) Fluorescent Tracer". Journal of Medicinal Chemistry 59 (10): 4849–58. May 2016. doi:10.1021/acs.jmedchem.6b00202. PMID 27074625. https://eprints.gla.ac.uk/118427/11/118427.pdf. 
  16. ↑ "The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids". The Journal of Biological Chemistry 278 (13): 11303–11. March 2003. doi:10.1074/jbc.M211495200. PMID 12496284. 
  17. ↑ "20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1". Nature Communications 9 (1): 177. January 2018. doi:10.1038/s41467-017-02539-4. PMID 29330456. Bibcode: 2018NatCo...9..177T. 
  18. ↑ "Immune regulation of poly unsaturated fatty acids and free fatty acid receptor 4". The Journal of Nutritional Biochemistry 112: 109222. February 2023. doi:10.1016/j.jnutbio.2022.109222. PMID 36402250. 
  19. ↑ "Dietary short-chain fatty acid intake improves the hepatic metabolic condition via FFAR3". Scientific Reports 9 (1): 16574. November 2019. doi:10.1038/s41598-019-53242-x. PMID 31719611. Bibcode: 2019NatSR...916574S. 
  20. ↑ "FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB". Cell & Bioscience 13 (1): 102. June 2023. doi:10.1186/s13578-023-01038-y. PMID 37287005. 
  21. ↑ "Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84". The Journal of Biological Chemistry 281 (45): 34457–64. November 2006. doi:10.1074/jbc.M608019200. PMID 16966319. 
  22. ↑ 22.0 22.1 "GPR84 in physiology-Many functions in many tissues". British Journal of Pharmacology. August 2023. doi:10.1111/bph.16206. PMID 37533166. 
  23. ↑ "Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors". Frontiers in Cellular Neuroscience 13: 162. 2019. doi:10.3389/fncel.2019.00162. PMID 31105530. 
  24. ↑ "20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?". DNA and Cell Biology 39 (11): 1926–1937. November 2020. doi:10.1089/dna.2020.5846. PMID 33001759. 
  25. ↑ "Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain". Neural Regeneration Research 18 (4): 763–768. April 2023. doi:10.4103/1673-5374.354514. PMID 36204834. 
  26. ↑ 26.0 26.1 "Molecular identification of high and low affinity receptors for nicotinic acid". The Journal of Biological Chemistry 278 (11): 9869–74. March 2003. doi:10.1074/jbc.M210695200. PMID 12522134. 
  27. ↑ "Short-chain fatty acid receptors and gut microbiota as therapeutic targets in metabolic, immune, and neurological diseases". Pharmacology & Therapeutics 239: 108273. November 2022. doi:10.1016/j.pharmthera.2022.108273. PMID 36057320. 
  28. ↑ "Participation of Short-Chain Fatty Acids and Their Receptors in Gut Inflammation and Colon Cancer". Frontiers in Physiology 12: 662739. 2021. doi:10.3389/fphys.2021.662739. PMID 33897470. 
  29. ↑ "Molecular identification of nicotinic acid receptor". Biochemical and Biophysical Research Communications 303 (1): 364–9. March 2003. doi:10.1016/s0006-291x(03)00342-5. PMID 12646212. 
  30. ↑ "Role of GPR81 in lactate-mediated reduction of adipose lipolysis". Biochemical and Biophysical Research Communications 377 (3): 987–91. December 2008. doi:10.1016/j.bbrc.2008.10.088. PMID 18952058. 
  31. ↑ "The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule". Nutrition & Metabolism 19 (1): 52. July 2022. doi:10.1186/s12986-022-00687-z. PMID 35907984. 
  32. ↑ "Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin". Biomolecules 11 (9): 1373. September 2021. doi:10.3390/biom11091373. PMID 34572586. 
  33. ↑ "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: 1–19. April 2023. doi:10.1080/10408398.2023.2203762. PMID 37096487. 
  34. ↑ "Metabolite-sensing GPCRs controlling interactions between adipose tissue and inflammation". Frontiers in Endocrinology 14: 1197102. 2023. doi:10.3389/fendo.2023.1197102. PMID 37484963. 
  35. ↑ 35.0 35.1 "Exploring GPR109A Receptor Interaction with Hippuric Acid Using MD Simulations and CD Spectroscopy". International Journal of Molecular Sciences 23 (23): 14778. November 2022. doi:10.3390/ijms232314778. PMID 36499106. 
  36. ↑ 36.0 36.1 "Production of Hydroxycarboxylic Acid Receptor 3 (HCA3) Ligands by Bifidobacterium". Microorganisms 9 (11): 2397. November 2021. doi:10.3390/microorganisms9112397. PMID 34835522. 
  37. ↑ "Succinate as a signaling molecule in the mediation of liver diseases". Biochimica et Biophysica Acta. Molecular Basis of Disease 1870 (2): 166935. November 2023. doi:10.1016/j.bbadis.2023.166935. PMID 37976628. 

External links



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