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

Overview

Journal Biomol Ther (Seoul)

Specialty Pharmacology

Date 2020 Dec 29

PMID 33372166

Citations 11

Authors

So-Eun Son

Nam-Jung Kim

Dong-Soon Im

Affiliations

Soon will be listed here.

Abstract

Till the 21 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 21 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.

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References

Sun Q, Hirasawa A, Hara T, Kimura I, Adachi T, Awaji T . Structure-activity relationships of GPR120 agonists based on a docking simulation. Mol Pharmacol. 2010; 78(5):804-10. DOI: 10.1124/mol.110.066324. View

Janssen S, Laermans J, Iwakura H, Tack J, Depoortere I . Sensing of fatty acids for octanoylation of ghrelin involves a gustatory G-protein. PLoS One. 2012; 7(6):e40168. PMC: 3387020. DOI: 10.1371/journal.pone.0040168. View

Moran B, Abdel-Wahab Y, Flatt P, McKillop A . Evaluation of the insulin-releasing and glucose-lowering effects of GPR120 activation in pancreatic β-cells. Diabetes Obes Metab. 2014; 16(11):1128-39. DOI: 10.1111/dom.12330. View

Engelstoft M, Park W, Sakata I, Kristensen L, Husted A, Osborne-Lawrence S . Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol Metab. 2013; 2(4):376-92. PMC: 3854997. DOI: 10.1016/j.molmet.2013.08.006. View

Zhao C, Zhou J, Meng Y, Shi N, Wang X, Zhou M . DHA Sensor GPR120 in Host Defense Exhibits the Dual Characteristics of Regulating Dendritic Cell Function and Skewing the Balance of Th17/Tregs. Int J Biol Sci. 2020; 16(3):374-387. PMC: 6990895. DOI: 10.7150/ijbs.39551. View

Azevedo C, Watterson K, Wargent E, Hansen S, Hudson B, Kepczynska M . Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity. J Med Chem. 2016; 59(19):8868-8878. DOI: 10.1021/acs.jmedchem.6b00685. View

Chen Y, Lin Y, Sun C, Huang T, Yip H, Chen Y . Extracorporeal shockwave against inflammation mediated by GPR120 receptor in cyclophosphamide-induced rat cystitis model. Mol Med. 2018; 24(1):60. PMC: 6260739. DOI: 10.1186/s10020-018-0062-1. View

Im D . Intercellular Lipid Mediators and GPCR Drug Discovery. Biomol Ther (Seoul). 2014; 21(6):411-22. PMC: 3879912. DOI: 10.4062/biomolther.2013.080. View

Christian M . Elucidation of the roles of brown and brite fat genes: GPR120 is a modulator of brown adipose tissue function. Exp Physiol. 2020; 105(8):1201-1205. PMC: 8650997. DOI: 10.1113/EP087877. View

10.

Li Z, Zhou Z, Zhang L . Current status of GPR40/FFAR1 modulators in medicinal chemistry (2016-2019): a patent review. Expert Opin Ther Pat. 2019; 30(1):27-38. DOI: 10.1080/13543776.2020.1698546. View

11.

Ulven T, Christiansen E . Dietary Fatty Acids and Their Potential for Controlling Metabolic Diseases Through Activation of FFA4/GPR120. Annu Rev Nutr. 2015; 35:239-63. DOI: 10.1146/annurev-nutr-071714-034410. View

12.

Stone V, Dhayal S, Brocklehurst K, Lenaghan C, Winzell M, Hammar M . GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans. Diabetologia. 2014; 57(6):1182-91. PMC: 4018485. DOI: 10.1007/s00125-014-3213-0. View

13.

Gong Z, Yoshimura M, Aizawa S, Kurotani R, Zigman J, Sakai T . G protein-coupled receptor 120 signaling regulates ghrelin secretion in vivo and in vitro. Am J Physiol Endocrinol Metab. 2013; 306(1):E28-35. DOI: 10.1152/ajpendo.00306.2013. View

14.

Takahashi K, Fukushima K, Onishi Y, Minami K, Otagaki S, Ishimoto K . Involvement of FFA1 and FFA4 in the regulation of cellular functions during tumor progression in colon cancer cells. Exp Cell Res. 2018; 369(1):54-60. DOI: 10.1016/j.yexcr.2018.05.005. View

15.

Han L, Song S, Niu Y, Meng M, Wang C . Eicosapentaenoic Acid (EPA) Induced Macrophages Activation through GPR120-Mediated Raf-ERK1/2-IKKβ-NF-κB p65 Signaling Pathways. Nutrients. 2017; 9(9). PMC: 5622697. DOI: 10.3390/nu9090937. View

16.

Hudson B, Shimpukade B, MacKenzie A, Butcher A, Pediani J, Christiansen E . The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism. Mol Pharmacol. 2013; 84(5):710-25. PMC: 3807074. DOI: 10.1124/mol.113.087783. View

17.

Hansen K, Rosenkilde M, Knop F, Wellner N, Diep T, Rehfeld J . 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J Clin Endocrinol Metab. 2011; 96(9):E1409-17. DOI: 10.1210/jc.2011-0647. View

18.

Kern P, Finlin B, Ross D, Boyechko T, Zhu B, Grayson N . Effects of KDT501 on Metabolic Parameters in Insulin-Resistant Prediabetic Humans. J Endocr Soc. 2017; 1(6):650-659. PMC: 5686568. DOI: 10.1210/js.2017-00202. View

19.

Yore M, Syed I, Moraes-Vieira P, Zhang T, Herman M, Homan E . Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell. 2014; 159(2):318-32. PMC: 4260972. DOI: 10.1016/j.cell.2014.09.035. View

20.

Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L . Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature. 2012; 483(7389):350-4. DOI: 10.1038/nature10798. View