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Review
. 2016 Jun 15:110-111:1-15.
doi: 10.1016/j.bcp.2016.01.021. Epub 2016 Jan 28.

Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders

Nader H Moniri  1
Affiliations
Review

Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders

Nader H Moniri. Biochem Pharmacol. .

Abstract

Over the last decade, a subfamily of G protein-coupled receptors that are agonized by endogenous and dietary free-fatty acids (FFA) has been discovered. These free-fatty acid receptors include FFA2 and FFA3, which are agonized by short-chained FFA, as well as FFA1 and FFA4, which are agonized by medium-to-long chained FFA. Ligands for FFA1 and FFA4 comprise the family of long chain polyunsaturated omega-3 fatty acids including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), suggesting that many of the long-known beneficial effects of these fats may be receptor mediated. In this regard, FFA4 has gathered considerable interest due to its role in ameliorating inflammation, promoting insulin sensitization, and regulating energy metabolism in response to FFA ligands. The goal of this review is to summarize the body of evidence in regard to FFA4 signal transduction, its mechanisms of regulation, and its functional role in a variety of tissues. In addition, recent endeavors toward discovery of small molecules that modulate FFA4 activity are also presented.

Keywords: Free fatty acids; Free-fatty acid receptor-4; G protein-coupled receptors; GPR120; Polyunsaturated fats.

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Figures

Figure 1:
Figure 1:. (A) Snake Diagram of FFA4-S and FFA4-L.
Numbers signify amino acid residues relative to initiating methionine. The insert shows the additional 16 amino acid gap within ICL3 of FFA4-L and corresponding numbering of FFA4-S/L residues after this point are noted. The amino acid residues shaded in red are implicated in ligand binding (R99, Y104, F115 F211, W207, W277, F304). The amino acids shaded in yellow are known phosphorylation sites (T347, T349, S350, S357, S361) of FFA4-S, which along with the noted acid residues (E341, D348, D355) shaded in green, create the β-arrestin phosphosensor. (B) Amino acid homology of rat, mouse, and human FFA4. Rat and mouse FFA4 share 98% sequence homology, while sequence homology of human FFA4-S with the rat and mouse protein is 85 and 86%, respectively. The percentage of homology (0–100%) at each amino acid residue across all four proteins is noted by the blue bar. Putative transmembrane helical (TMH) domains are noted.
Figure 1:
Figure 1:. (A) Snake Diagram of FFA4-S and FFA4-L.
Numbers signify amino acid residues relative to initiating methionine. The insert shows the additional 16 amino acid gap within ICL3 of FFA4-L and corresponding numbering of FFA4-S/L residues after this point are noted. The amino acid residues shaded in red are implicated in ligand binding (R99, Y104, F115 F211, W207, W277, F304). The amino acids shaded in yellow are known phosphorylation sites (T347, T349, S350, S357, S361) of FFA4-S, which along with the noted acid residues (E341, D348, D355) shaded in green, create the β-arrestin phosphosensor. (B) Amino acid homology of rat, mouse, and human FFA4. Rat and mouse FFA4 share 98% sequence homology, while sequence homology of human FFA4-S with the rat and mouse protein is 85 and 86%, respectively. The percentage of homology (0–100%) at each amino acid residue across all four proteins is noted by the blue bar. Putative transmembrane helical (TMH) domains are noted.
Figure 2:
Figure 2:
Known physiological effects of FFA4 agonism.
Figure 3:
Figure 3:. Anti-inflammatory FFA4 signaling pathways in macrophages.
LPS and TNF-α are well known to promote inflammatory processes via activation of Toll-like receptor 4 (TLR4) and TNF-receptor (TNFR), respectively. Activation of either receptor causes the interaction of TAK1 kinase and its binding protein TAB1, activating the TAK1 complex. Active TAK1 phosphorylates MKK4 leading to phosphorylation of JNK. TAK1 can also phosphorylate IK-kinase-β which then phosphorylates IKB, releasing its ability to inhibit NF-κB. Phosphorylated IKB is ubiquitinated and degraded, thereby promoting further activity of NF-κB due to the loss of the inhibitor. NF-κB and phospho-JNK promote downstream inflammatory processes, including increased expression of TNF-α, IL-6, IL-1β, COX2, MCP-1, iNOS, and CD11c. Agonism of FFA4 leads to β-arrestin-2 recruitment, which sequesters TAB1, thereby, inhibiting its interaction with TAK1. Loss of this interaction inhibits downstream activation of NF-κB and JNK, and promotes anti-inflammatory effects, and can also facilitate expression of anti-inflammatory mediators such as Arginase-1, IL-10, and MGL1. Furthermore, FFA4-dependent β-arrestin recruitment inhibits AKT signaling, again, inhibiting the activation of NF-κB, thereby promoting anti-inflammatory effects. Finally, activation of FFA4 activation, via both Gαq/11 and β-arrestin-2, facilitates ERK1/2-dependent PGE2 synthesis, which can then act via prostaglandin EP4 receptors to inhibit NF-κB-modulated inflammatory effects.
Figure 4:
Figure 4:
Structures of reported FFA4 antagonists.
See this image and copyright information in PMC

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