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Review
. 2021 Jan 1;29(1):22-30.
doi: 10.4062/biomolther.2020.213.

Development of Free Fatty Acid Receptor 4 (FFA4/GPR120) Agonists in Health Science

So-Eun Son  1 , Nam-Jung Kim  1 , Dong-Soon Im  1
Affiliations
Review

Development of Free Fatty Acid Receptor 4 (FFA4/GPR120) Agonists in Health Science

So-Eun Son et al. Biomol Ther (Seoul). .

Abstract

Till the 21st century, fatty acids were considered as merely building blocks for triglycerides, phospholipids, or cholesteryl esters. However, the discovery of G protein-coupled receptors (GPCRs) for free fatty acids at the beginning of the 21st century challenged that idea and paved way for a new field of research, merged into the field of receptor pharmacology for intercellular lipid mediators. Among the GPCRs for free fatty acids, free fatty acid receptor 4 (FFA4, also known as GPR120) recognizes long-chain polyunsaturated fatty acids such as DHA and EPA. It is significant in drug discovery because it regulates obesity-induced metaflammation and GLP-1 secretion. Our study reviews information on newly developed FFA4 agonists and their application in pathophysiologic studies and drug discovery. It also offers a potency comparison of the FFA4 agonists in an AP-TGF-α shedding assay.

Keywords: Agonist; Drug development; FFA4; G protein-coupled receptor; GPR120.

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Figures

Fig. 1
Fig. 1
Structures of FFA4 agonists and antagonist. DHA, EPA, pinolenic acid, 9-PAHSA, GW9508, grifolic acid, NCG21, compound A, TUG891, metabolex 36, and compound B have a carboxylic acid moiety, while GSK137647A, TUG-1197, KDT501 and AH-7614 have a sulfone amide moiety or an enolic acid moiety.
Fig. 2
Fig. 2
Concentration-response curves of FFA4 agonists in an AP-TGF-α shedding assay. HEK-293 cells were transfected with plasmids (an AP fusion protein of TGF-α and human FFA4) using Lipofectamine 2000 (Thermo Fisher Scientific, Waltham, MA, USA). The following day, ligands were added at different concentrations in transfected HEK-293 cells, and the plate was incubated for 1 h. Para-nitrophenyl phosphate (substrate of AP)-containing solution was added to the conditioned medium plate and to the cell plate. The absorbance of the plate contents was measured for 405 nm. The ratio of the two absorbance values was used as a measure of GPCR activation (Inoue et al., 2012).
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