Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like G-protein coupled receptor[5] that is coded (i.e., its synthesis is directed) by the FFAR1 gene.[6] This gene is located on the short (i.e., "q") arm of chromosome 19 at position 13.12 (location notated as 19q13.12).[7] G protein-coupled receptors (also termed GPRs or GPCRs) reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells.[5] FFAR1 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes at least three other FFARs viz., FFAR2 (also termed GPR43), FFAR3 (also termed GPR41), and FFAR4 (also termed GPR120). FFARs bind and thereby are activated by certain fatty acids.[8]
Studies suggest that FFAR1 may be involved in the development of obesity, type 2 diabetes,[9][10] and various emotional, behavioral, learning, and cognition defects[11] such as Alzheimer's disease.[12] FFAR1 may also be involved in the perception of pain, the tastes of and preferences for eating fatty and sweet foods,[9] the pathological replacement of injured tissue with fibrosis and scarring,[13] and the malignant behavior, i.e., proliferation, invasiveness, and metastasis, of some types of cancer cells.[14]
Various fatty acids, including in particular two omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids,[11] have been consumed in diets and supplements for the purposes of preventing or treating the disorders that recent studies suggest are associated with abnormalities in FFAR1's functions. It is now known that these fatty acids activate (i.e. are agonists of) FFAR1 as well as FFAR4. While dietary and supplemental omega-3 fatty acids have had no or only marginally significant therapeutic effects on these disorders (see health effects of omega-3 fatty acid supplementation), drugs have been developed that are more potent and selective in activating FFAR1 than the omega-3 fatty acids.[11][15][16] Furthermore, drugs have been developed that potently inhibit (i.e. are antagonists of) FFAR1.[15] This raised the possibility that the drugs may be more effective than the omega-3 fatty acids in treating these diseases and prompted studies testing their effectiveness to do so.[17] These studies, which are preclinical studies on cultured cells and animal models of disease plus some clinical studies, are detailed here.
^ abcGRCh38: Ensembl release 89: ENSG00000126266 – Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000044453 – Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ abWeis WI, Kobilka BK (June 2018). "The Molecular Basis of G Protein-Coupled Receptor Activation". Annual Review of Biochemistry. 87: 897–919. doi:10.1146/annurev-biochem-060614-033910. PMC 6535337. PMID 29925258.
^"Entrez Gene: FFAR1 free fatty acid receptor 1".
^Kalis M, Levéen P, Lyssenko V, Almgren P, Groop L, Cilio CM (November 2007). "Variants in the FFAR1 gene are associated with beta cell function". PLOS ONE. 2 (11): e1090. Bibcode:2007PLoSO...2.1090K. doi:10.1371/journal.pone.0001090. PMC 2042513. PMID 17987108.
^Karmokar 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. PMID 36309079. S2CID 253174629.
^ abKimura I, Ichimura A, Ohue-Kitano R, Igarashi M (January 2020). "Free Fatty Acid Receptors in Health and Disease". Physiological Reviews. 100 (1): 171–210. doi:10.1152/physrev.00041.2018. PMID 31487233. S2CID 201845937.
^Secor JD, Fligor SC, Tsikis ST, Yu LJ, Puder M (2021). "Free Fatty Acid Receptors as Mediators and Therapeutic Targets in Liver Disease". Frontiers in Physiology. 12: 656441. doi:10.3389/fphys.2021.656441. PMC 8058363. PMID 33897464.
^ abcDuah 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. PMID 36402250. S2CID 253652038.
^Governa P, Caroleo MC, Carullo G, Aiello F, Cione E, Manetti F (June 2021). "FFAR1/GPR40: One target, different binding sites, many agonists, no drugs, but a continuous and unprofitable tug-of-war between ligand lipophilicity, activity, and toxicity". Bioorganic & Medicinal Chemistry Letters. 41: 127969. doi:10.1016/j.bmcl.2021.127969. PMID 33771587. S2CID 232375863.
^Gagnon L, Leduc M, Thibodeau JF, Zhang MZ, Grouix B, Sarra-Bournet F, Gagnon W, Hince K, Tremblay M, Geerts L, Kennedy CR, Hébert RL, Gutsol A, Holterman CE, Kamto E, Gervais L, Ouboudinar J, Richard J, Felton A, Laverdure A, Simard JC, Létourneau S, Cloutier MP, Leblond FA, Abbott SD, Penney C, Duceppe JS, Zacharie B, Dupuis J, Calderone A, Nguyen QT, Harris RC, Laurin P (May 2018). "A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84". The American Journal of Pathology. 188 (5): 1132–1148. doi:10.1016/j.ajpath.2018.01.009. PMID 29454750.
^Senatorov IS, Moniri NH (April 2018). "The role of free-fatty acid receptor-4 (FFA4) in human cancers and cancer cell lines". Biochemical Pharmacology. 150: 170–180. doi:10.1016/j.bcp.2018.02.011. PMC 5866782. PMID 29452095.
^ abGrundmann M, Bender E, Schamberger J, Eitner F (February 2021). "Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators". International Journal of Molecular Sciences. 22 (4): 1763. doi:10.3390/ijms22041763. PMC 7916689. PMID 33578942.
^Son SE, Kim NJ, Im DS (January 2021). "Development of Free Fatty Acid Receptor 4 (FFA4/GPR120) Agonists in Health Science". Biomolecules & Therapeutics. 29 (1): 22–30. doi:10.4062/biomolther.2020.213. PMC 7771848. PMID 33372166.
^Lay AC (October 2021). "Does FFAR4 Agonism have Therapeutic Potential in Cardiometabolic Disease?". Endocrinology. 162 (10). doi:10.1210/endocr/bqab145. PMC 8354430. PMID 34282845.
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