Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-likeG-protein coupled receptor[5] that is coded (i.e., its synthesis is directed) by the FFAR1gene.[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.
^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. PMID36309079. S2CID253174629.
^ 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. PMID36402250. S2CID253652038.
^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. PMID33771587. S2CID232375863.
^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. PMID29454750.
