Surf Wiki
Save to docs
general/g-protein-coupled-receptors

From Surf Wiki (app.surf) — the open knowledge base

Free fatty acid receptor

G-protein coupled receptor which binds free fatty acids

Summary

G-protein coupled receptor which binds free fatty acids

FieldValue
Namefree fatty acid receptor 1
HGNCid4498
SymbolFFAR1, FFA1R
AltSymbolsGPR40
EntrezGene2864
OMIM603820
RefSeqNM_005303
UniProtO14842
Chromosome19
Armq
Band13.1

Free fatty acid receptors (FFARs) are G-protein coupled receptors (GPRs). 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. Humans express more than 800 different types of GPCRs. 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). 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.

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

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. β-hydroxybutyric acid has been reported to stimulate or inhibit FFAR3. 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 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, and 20-hydroxyeicosatetraenoic acids. Among the fatty acids that activate FFAR1 and FFAR4, docosahexaenoic and eicosapentaenoic acids are regarded as the main fatty acids that do so.

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.

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. It has been recognized as a possible member of the free fatty acid receptor family in some publications 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. Consequently, GPR89 remains classified as an orphan receptor, i.e., a receptor who's naturally occurring activator(s) is unclear.

GPR109A is also termed hydroxycarboxylic acid receptor 2, niacin receptor 1, HM74a, HM74b, and PUMA-G. GPR109A binds and thereby is activated by the short-chain fatty acids, butyric, β-hydroxybutyric, pentanoic and hexanoic acids and by the intermediate-chain fatty acids heptanoic and octanoic acids. 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.

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 and β-hydroxybutyric acid. A more recent study reported that it is also activated by the compound 3,5-dihydroxybenzoic acid.

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, niacin, and by four compounds viz., hippuric acid, 4-hydroxyphenyllactic acid, phenyllacetic acid, and indole-3-lactic acid. The latter three compounds are produced by Lactobacillus and Bifidobacterium species of bacteria that occupy the gastrointestinal tracts of animals and humans.

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.

References

References

  1. (2006). "The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensing". Biochem. Soc. Trans..
  2. (June 2018). "The Molecular Basis of G Protein-Coupled Receptor Activation". Annual Review of Biochemistry.
  3. (December 2021). "Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment". Biomedicine & Pharmacotherapy.
  4. (December 2022). "Oncogenic signaling of the free-fatty acid receptors FFA1 and FFA4 in human breast carcinoma cells". Biochemical Pharmacology.
  5. (2021). "Free Fatty Acid Receptors as Mediators and Therapeutic Targets in Liver Disease". Frontiers in Physiology.
  6. (April 2021). "Allosteric targeting of the FFA2 receptor (GPR43) restores responsiveness of desensitized human neutrophils". Journal of Leukocyte Biology.
  7. (March 2003). "The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids". The Journal of Biological Chemistry.
  8. (November 2009). "Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42". DNA and Cell Biology.
  9. (August 2015). "Human GPR42 is a transcribed multisite variant that exhibits copy number polymorphism and is functional when heterologously expressed". Scientific Reports.
  10. (April 2017). "Microbial Short-Chain Fatty Acids and Blood Pressure Regulation". Current Hypertension Reports.
  11. (February 2012). "Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human". Nature.
  12. (January 2018). "FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing". FASEB Journal.
  13. (January 2020). "Free Fatty Acid Receptors in Health and Disease". Physiological Reviews.
  14. (December 2013). "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.
  15. (May 2016). "Development and Characterization of a Potent Free Fatty Acid Receptor 1 (FFA1) Fluorescent Tracer". Journal of Medicinal Chemistry.
  16. (March 2003). "The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids". The Journal of Biological Chemistry.
  17. (January 2018). "20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1". Nature Communications.
  18. (February 2023). "Immune regulation of poly unsaturated fatty acids and free fatty acid receptor 4". The Journal of Nutritional Biochemistry.
  19. (November 2019). "Dietary short-chain fatty acid intake improves the hepatic metabolic condition via FFAR3". Scientific Reports.
  20. (June 2023). "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.
  21. (November 2006). "Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84". The Journal of Biological Chemistry.
  22. (August 2023). "GPR84 in physiology-Many functions in many tissues". British Journal of Pharmacology.
  23. (2019). "Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors". Frontiers in Cellular Neuroscience.
  24. (November 2020). "20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?". DNA and Cell Biology.
  25. (April 2023). "Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain". Neural Regeneration Research.
  26. (March 2003). "Molecular identification of high and low affinity receptors for nicotinic acid". The Journal of Biological Chemistry.
  27. (November 2022). "Short-chain fatty acid receptors and gut microbiota as therapeutic targets in metabolic, immune, and neurological diseases". Pharmacology & Therapeutics.
  28. (2021). "Participation of Short-Chain Fatty Acids and Their Receptors in Gut Inflammation and Colon Cancer". Frontiers in Physiology.
  29. (March 2003). "Molecular identification of nicotinic acid receptor". Biochemical and Biophysical Research Communications.
  30. (December 2008). "Role of GPR81 in lactate-mediated reduction of adipose lipolysis". Biochemical and Biophysical Research Communications.
  31. (July 2022). "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.
  32. (September 2021). "Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin". Biomolecules.
  33. (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.
  34. (2023). "Metabolite-sensing GPCRs controlling interactions between adipose tissue and inflammation". Frontiers in Endocrinology.
  35. (November 2022). "Exploring GPR109A Receptor Interaction with Hippuric Acid Using MD Simulations and CD Spectroscopy". International Journal of Molecular Sciences.
  36. (November 2021). "Production of Hydroxycarboxylic Acid Receptor 3 (HCA3) Ligands by Bifidobacterium". Microorganisms.
  37. (November 2023). "Succinate as a signaling molecule in the mediation of liver diseases". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
Wikipedia Source

This article was imported from Wikipedia and is available under the Creative Commons Attribution-ShareAlike 4.0 License. Content has been adapted to SurfDoc format. Original contributors can be found on the article history page.

g-protein-coupled-receptors
Want to explore this topic further?

Ask Mako anything about Free fatty acid receptor — get instant answers, deeper analysis, and related topics.

Research with Mako

Free with your Surf account

Content sourced from Wikipedia, available under CC BY-SA 4.0.

This content may have been generated or modified by AI. CloudSurf Software LLC is not responsible for the accuracy, completeness, or reliability of AI-generated content. Always verify important information from primary sources.

Report