The physiological functions of various fatty acid-originating metabolites from foods and fermented products remained mostly untouched. Thereby, this study examined the biological activities of hydroxy fatty acids as agonists of G protein-coupled receptors (i.e., GPR40 and GPR120), which are derived from long-chain fatty acids (e.g., oleic acid and linoleic acid) by microbiota. Cell-based Ca2+ mobilization assays and in silico docking simulations revealed that not only the degree of unsaturation but also the number and position of hydroxyl groups played a key role in their agonist activities. For instance, 8,11-dihydroxyoctadec-9Z-enoic acid exhibited significantly greater Ca2+ response in the GPR40/GPR120-expressing cells as compared to the endogenous agonists (e.g., linoleic acid and docosahexaenoic acid), forming hydrogen bond interactions with residues in the ligand-binding pockets of receptors. This study will contribute to understanding the relationships between fatty acid structures and agonist activities.
Keywords: Dual agonists; Free fatty acid receptors; GPR120 (FFAR4); GPR40 (FFAR1); Hydroxy fatty acids.
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