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  • br FFA GPR was deorphanised as the second receptor for

    2021-12-01


    FFA4 GPR120 was deorphanised as the second receptor for long-chain fatty acids in 2005 [5]. Initial focus highlighted expression in the lower gut, the capacity of unsaturated fatty acids to promote release of the incretin glucagon-like peptide-1 (GLP-1) from the enteroendocrine cell line STC-1, and that both fatty acid-mediated elevation of phosphorylated extracellular regulated kinase (ERK) 1/2 MAP kinases and internalisation of the receptor from the surface of transfected cells could be used effectively as means to screen for, and identify, synthetic agonists at the receptor [5]. These initial studies also highlighted the importance of the carboxylate of the fatty acids to their function because equivalent methyl esters were inactive. Although the authors also reported [5] the ability of α-linolenic PEG Virus Precipitation Kit [18:3(n-3); Box 1] to increase levels of both GLP-1 and insulin in both the portal vein and inferior vena cava of mice, there remains uncertainty over the contribution of such released GLP-1 to the observed increase in circulating insulin levels and whether this is also the case in humans. Of particular interest, although not explored further in the initial studies, was the observation of particularly high levels of receptor mRNA in the lung of both humans and mice [5]. The potential relevance of this is discussed below. Although only distantly related in terms of sequence to FFA1, acceptance of GPR120 as a bona fide GPCR responsive to long-chain fatty acids resulted in its systematic re-classification as FFA4 [7]. Although detailed and comprehensive analyses have shown that a broad swathe of saturated as well as unsaturated fatty acids are able to activate FFA4 [20] (reviewed in [3]), initial description of the capacity of α-linolenic acid to activate this receptor paved the way for a particular focus on the effects of this and other health-beneficial omega-3 fatty acids acting either predominantly, or even exclusively, via FFA4 21, 22, 23, 24, 25, 26, 27, 28. This is undoubtedly an oversimplification. For example, there have been suggestions that several beneficial effects of omega-3 fatty acids do not require FFA4 29, 30, 31, 32, 33. However, it is important to note equivalent studies where using combinations of FFA4 expression knockout and animals that synthesise high levels of polyunsaturated omega-3 fatty acids, resulted in the suggestion that such fatty acids regulate beneficially vascular inflammation and neointimal hyperplasia via FFA4 [34]. A challenge for the translation of these ideas to humans is whether, even with dietary supplementation, levels of such fatty acids are likely sufficient to engage the receptor to a substantial level [35]. This question is further complicated by the fact that quantitatively more prevalent fatty acids are also able to activate FFA4 [20], while specific, but relatively uncommon, fatty acids or their derivatives, which do not display substantially greater potency at FFA4 in vitro, are capable of generating biological functions with apparent high potency and that are lacking in FFA4-knockout animals [36] or are reduced with knock down of this receptor in model cell systems [37].
    Signalling Mechanisms of FFA4
    Synthetic Agonists for FFA4 Long-chain fatty acids can be rapidly converted to different biologically active species that function at GPCRs other than FFA1 and/or FFA4. Given that such interconversion is challenging to limit in vivo, direct studies with fatty acids can be difficult to interpret unequivocally. As such, the identification and characterisation of synthetic ligands with affinity for FFA4 have been integral to better understanding the biological functions of this receptor (Table 1). However, owing to the strongly overlapping profile of fatty acids as activators of FFA4 and FFA1, many of the initially described synthetic ligands with activity at FFA4 are also able to activate FFA1 (Table 1). This reflects their structural similarity to fatty acids. More recently described ligands display improved selectivity for FFA4 over FFA1 (Table 1).