Free fatty acid receptor 4

FFAR4
Identifiers
AliasesFFAR4, BMIQ10, GPR120, GPR129, GT01, O3FAR1, PGR4, free fatty acid receptor 4
External IDsOMIM: 609044; MGI: 2147577; HomoloGene: 18769; GeneCards: FFAR4; OMA:FFAR4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

338557

107221

Ensembl

ENSG00000186188

ENSMUSG00000054200

UniProt

Q5NUL3

Q7TMA4

RefSeq (mRNA)

NM_001195755
NM_181745

NM_181748

RefSeq (protein)

NP_001182684
NP_859529

NP_861413

Location (UCSC)Chr 10: 93.57 – 93.6 MbChr 19: 38.09 – 38.1 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Free Fatty acid receptor 4 (FFAR4), also termed G-protein coupled receptor 120 (GPR120), is a protein that in humans is encoded (i.e., its formation is directed) by the FFAR4 gene.[5] This gene is located on the long (i.e. "P") arm of chromosome 10 at position 23.33 (position notated as 10q23.33). 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.[6] FFAR4 is a rhodopsin-like GPR in the broad family of GPRs[7] which in humans are encoded by more than 800 different genes.[8] It is also a member of a small family of structurally and functionally related GPRs that include at least three other free fatty acid receptors (FFARs) viz., FFAR1 (also termed GPR40), FFAR2 (also termed GPR43), and FFAR3 (also termed GPR41). These four FFARs bind and thereby are activated by certain fatty acids.[9]

FFAR4 protein is expressed in a wide range of cell types. Studies conducted primarily on human and rodent cultured cells and in animals (mostly rodents) suggest that FFAR4 acts in these cells to regulate many normal bodily functions such as food preferences, food consumption, food tastes, body weight, blood sugar (i.e., glucose) levels, inflammation, atherosclerosis, and bone remodeling. Studies also suggest that the stimulation or suppression of FFAR4 alters the development and progression of several types of cancers.[10] In consequence, agents that activate or inhibit FFAR4 may be useful for treating excessive fatty food consumption, obesity, type 2 diabetes, pathological inflammatory reactions, atherosclerosis, atherosclerosis-induced cardiovascular disease, repair of damaged bones,[11] osteoporosis.[12][13] and some cancers.[10] These findings have made FFAR4 a potentially attractive therapeutic biological target for treating these disorders[11] and therefore lead to the development of drugs directed at regulating FFAR4's activities.[14][15]

Certain fatty acids, including in particular the omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids,[16] have been taken in diets and supplements to prevent or treat the diseases and tissue injuries that recent studies suggest are associated with abnormalities in FFAR4's functions. It is now known that these fatty acids activate FFAR4. While dietary and supplemental omega-3 fatty acids have had little or only marginal therapeutic effects on these disorders (see health effects of omega-3 fatty acid supplementation), many drugs have been found that are more potent and selective in activating FFAR4 than the omega-3 fatty acids[16][14] and one drug is a potent inhibitor of FFAR4.[15] This raised a possibility that the drugs may be more effective in treating these disorders[11] and prompted initial studies testing the effectiveness of them in disorders targeted by the omega-3 fatty acids.[17] These studies, which are mostly preclinical studies on cultured cells or animal models of disease with only a few preliminary clinical studies, are reviewed here.

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000186188 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000054200 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Codoñer-Alejos A, Carrasco-Luna J, Carrasco-García Á, Codoñer-Franch P (April 2022). "Reduced Free Fatty Acid Receptor 4 Gene Expression is Associated With Extreme Obesity and Insulin Resistance in Children". Journal of Pediatric Gastroenterology and Nutrition. 74 (4): 535–540. doi:10.1097/MPG.0000000000003360. PMID 35703949. S2CID 244894271.
  6. ^ Weis 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.
  7. ^ Fredriksson R, Höglund PJ, Gloriam DE, Lagerström MC, Schiöth HB (November 2003). "Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives". FEBS Letters. 554 (3): 381–8. doi:10.1016/s0014-5793(03)01196-7. PMID 14623098. S2CID 11563502.
  8. ^ Liang C, Li J, Tian B, Tian L, Liu Y, Li J, Xin L, Wang J, Fu C, Shi Z, Xia J, Liang Y, Wang K (December 2021). "Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment". Biomedicine & Pharmacotherapy. 144: 112298. doi:10.1016/j.biopha.2021.112298. PMID 34649219. S2CID 238990829.
  9. ^ 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.
  10. ^ a b 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.
  11. ^ a b c Stuttgen GM, Sahoo D (August 2021). "FFAR4: A New Player in Cardiometabolic Disease?". Endocrinology. 162 (8). doi:10.1210/endocr/bqab111. PMC 8218936. PMID 34043793.
  12. ^ Cite error: The named reference pmid26827942 was invoked but never defined (see the help page).
  13. ^ Wang Y, Liu H, Zhang Z (February 2023). "Recent Advance in Regulatory Effect of GRP120 on Bone Metabolism". Aging and Disease. 14 (5): 1714–1727. doi:10.14336/AD.2023.0216. PMC 10529742. PMID 37196107.
  14. ^ a b 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.
  15. ^ a b Grundmann 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.
  16. ^ a b Duah 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.
  17. ^ 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.