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Gene and Protein Information ![]() |
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class A G protein-coupled receptor | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 7 | 361 | 10q23.33 | FFAR4 | free fatty acid receptor 4 | 11,17 |
Mouse | 7 | 361 | 19 C2 | Ffar4 | free fatty acid receptor 4 | 11 |
Rat | 7 | 361 | 1q53 | Ffar4 | free fatty acid receptor 4 | 49 |
Database Links ![]() |
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Specialist databases | |
GPCRdb | ffar4_human (Hs), ffar4_mouse (Mm), ffar4_rat (Rn) |
Other databases | |
Alphafold | Q5NUL3 (Hs), Q7TMA4 (Mm), Q2AC31 (Rn) |
ChEMBL Target | CHEMBL5339 (Hs), CHEMBL2052036 (Mm), CHEMBL3309099 (Rn) |
Ensembl Gene | ENSG00000186188 (Hs), ENSMUSG00000054200 (Mm), ENSRNOG00000021763 (Rn) |
Entrez Gene | 338557 (Hs), 107221 (Mm), 294075 (Rn) |
Human Protein Atlas | ENSG00000186188 (Hs) |
KEGG Gene | hsa:338557 (Hs), mmu:107221 (Mm), rno:294075 (Rn) |
OMIM | 609044 (Hs) |
Pharos | Q5NUL3 (Hs) |
RefSeq Nucleotide | NM_181745 (Hs), NM_181748 (Mm), NM_001047088 (Rn) |
RefSeq Protein | NP_859529 (Hs), NP_861413 (Mm), NP_001040553 (Rn) |
UniProtKB | Q5NUL3 (Hs), Q7TMA4 (Mm), Q2AC31 (Rn) |
Wikipedia | FFAR4 (Hs) |
Selected 3D Structures ![]() |
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Natural/Endogenous Ligands ![]() |
linoleic acid |
α-linolenic acid |
myristic acid |
oleic acid |
Free fatty acids |
Download all structure-activity data for this target as a CSV file
Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The FFA4 receptor is a specific receptor for long-chain endogenous FFAs (α-linolenic acid, palmitoleic acid and docosahexaenoic acid) and can potently regulate the secretion of incretin hormone GLP-1 from the gastrointestinal tract [1,17]. For human and mouse FFA4 receptors isolated from DNA fragments, stimulatory activities were detected for saturated FFAs with chain length of C14 to C18, and for unsaturated FFAs with chain length of C16 to C22 [17]. FFA4 receptors can be activated by various saturated free fatty acids ranging in chain length from C14 to C18, as well as by both mono- and poly-unsaturated free fatty acids with chain lengths of between 16 and 22 carbon atoms [33]. Agonism with α-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human FFA4 receptor in HEK293 cells. Both receptor isoforms are phosphorylated to the same extent over a range of stimulation times, although the long isoform exhibits a lower basal level of phosphorylation [4]. A selective partial agonist has been identified among a series of natural compounds derived from fruiting bodies of Albatrellus ovinu. This compound could activate the FFA4 receptor in both FFA4 receptor overexpressing cells and STC-1 cells, which express FFA4 receptors endogenously [15]. A docking simulation approach using FFA1 and FFA4 receptor homology models could be useful in predicting the FFA1-selective agonistic activity of compounds [47]. A close analogue of 4-{4-[2-(phenyl-2-pyridinylamino)ethoxy]phenyl}butyric acid, 3-(4-{2-[phenyl(pyridin-2-yl)amino]ethoxy}phenyl)propanoic acid (compound 10), is also shown to be a weak non-selective agonist at FFA4 receptors [46], while synthetic ligand NCG120 has been shown to be an agonist for FFA4 receptors [15,45]. |
Antagonist Comments | ||
EPA is thought to bind to FFA4 receptors in the intestine inhibiting GLP-1 secretion, with potential as an anti-diabetic [34]. NCG21 activates extracellular signal-regulated kinase in a cloned FFA4 receptor system, and furthermore activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express FFA4 receptors endogenously. Administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds [45]. |
Immunopharmacology Comments |
FFA4 has been identified as a drug target in asthma and COPD [39]. A selective FFA4 agonist, TUG-1197 [2], reduced airway resistance in preclinical models of lung inflammation. |
Immuno Process Associations | ||
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Primary Transduction Mechanisms ![]() |
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Transducer | Effector/Response |
Gq/G11 family | |
Comments: Linolenic acid-mediated inhibition of Caspase-3 activity is mediated through the Gq pathway, but not the Gi nor the Gs pathway. Results suggest that FFA4 receptor activation leads to association of β-arrestin2 with the receptor and that this complex subsequently internalizes, whereupon β-arrestin2 can bind to TAB1 [37]. | |
References: 15,17,22 |
Tissue Distribution ![]() |
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Tissue Distribution Comments | ||||||||||
FFA4 receptors are also reported to be present in enteroendocrine cells (technique not specified) [40]. QPCR analysis show that pure L cells express the long chain fatty acid receptors GPR40, in addition to FFA4 receptors [10]. A high fat diet significantly up-regulates FFA4 receptor gene transcripts in rat cardiac tissue and extensor digitorum longus skeletal muscle [7]. Also rats sensitive to diet induced obesity show upregulation of FFA4 receptor, compared to resistant rats [9], and this is mirrored in humans [20]. A high-fat diet also increases the expression of this receptor on macrophages in mice [42]. FFA4 receptor expression displays a diurnal rhythm in the gustatory circumvallate papillae [28]. FFA4 receptor expression has also been found to be upregulated in obese humans [52]. Morgan and Dhayal found that FFA4 receptor is expressed in islets cells (data not published) [33]. In addition to numerous tissue distribution studies, the FFA4 receptor has also been shown to be expressed in various cells lines: Mouse GLUTag cells by RT-PCR analysis [41]. Human RAW264.7 cells by RT-PCR analysis [8]. Rat β-cell lines (INS-1, BRIN-BD11) (unpublished data) [33]. Breast cancer cell lines: Human MDA-MB-231 breast cancer cells, detected by flow cytometry [34]; human MCF-7 cells, MCF10A cells, also detected by flow cytometry [44] Despite expression in human epithelial breast cancer lines it is thought that the FFA4 receptor does not participate in the signal transduction pathways and in the cellular processes induced by arachidonic acid [34], or oleic acid in MCF10A cells [44]. Expression of FFA4 receptor protein and mRNA is up-regulated during the adipogenic differentiation of 3T3-L1 cells [32]. It seems likely that the shorter form of the FFA4 receptor is the major isoforms present in the endocrine pancreas, although FFA4 receptor agonists on insulin secretion are likely to be mediated mainly by indirect actions on the intestine [33]. |
Expression Datasets ![]() |
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Functional Assays ![]() |
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Functional Assay Comments | ||||||||||
Cell-based fluorescence imaging system successfully monitored the internalization of the FFA4 receptor [12]. Mice receiving bone marrow transplants from the FFA4 receptor-deficient mice are also resistant to the beneficial properties of DHA and EPA [42]. Although the FFA4 receptor has been characterized in LβT2 cells, it does not mediate the effects of unsaturated fatty acids on LH release [13]. |
Physiological Functions ![]() |
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Physiological Functions Comments | ||||||||
There is a suggested role for FFA4 in sensing dietary fat, based on expression in the taste cells of the circumvallate papillae and enteroendocrine cells [30]. FFA4 triggers release of incretins from intestinal endocrine cells, and so indirectly enhances insulin secretion and promote satiety. FFA4 signaling in adipocytes and macrophages also results in insulin sensitizing and beneficial anti-inflammatory effects [19]. |
Physiological Consequences of Altering Gene Expression ![]() |
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Physiological Consequences of Altering Gene Expression Comments | ||||||||||
It is possible that the relative levels of O3FAR1 expression in STC-1 cells does not necessarily reflect the levels expressed in the native I cell, and further studies on native I cells will be necessary to exclude a potential role of FFA4 on CCK secretion [25]. O3FAR1 gene inactivation leads to a decrease in the preference for lipids [28]. |
Phenotypes, Alleles and Disease Models ![]() |
Mouse data from MGI | ||||||||||||||||||||||||
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Clinically-Relevant Mutations and Pathophysiology ![]() |
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Clinically-Relevant Mutations and Pathophysiology Comments | ||||||||||||||||||||||||||
O3FAR1 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits FFA4 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in european populations [20,31]. |
Biologically Significant Variants ![]() |
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Biologically Significant Variant Comments | ||||||||||||||||||
Long (L, Q5NUL3-1) and short (S, Q5NUL3-2) human FFA4 splice variants, differ by insertion of 16 amino acids in the third intracellular loop. The third intracellular loop insertion in FFA4L prevents G protein-dependent intracellular calcium and DMR responses, but this receptor isoform remains functionally coupled to the β-arrestin pathway, providing one of the first examples of a native β-arrestin-biased receptor [50]. |
General Comments |
The Arg, Asn/His, and Arg residues at the top of TM5, TM6, and TM7, anchoring the carboxylate group in FFA1-3 receptors are absent in the FFA4 receptor, suggesting that the binding mode of FFAs in the FFA4 receptor is different from FFA1-3 receptors [51]. The FFA4 receptor regulates the secretion of glucagon-like peptide-1 in the intestine, as well as insulin sensitivity in macrophages [15]. |
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