Investigation of the Inhibitory Effects of Fatty Acid Derivatives on URAT1 Function, a Renal Urate Re-Absorber.

Abstract

The global increase in hyperuricemia, a pathological condition characterized by elevated serum urate concentrations, emphasizes the importance of appropriate management of uric acid homeostasis in the body. Enhancing renal urate excretion is clinically relevant to achieve serum urate-lowering, and the functional inhibition of urate transporter 1 (URAT1), a renal urate transporter involved in the reabsorption of urate, has been recognized as a promising strategy. In this context, natural substances, including food ingredients with URAT1-inhibitory activity, have garnered significant interest. A previous study demonstrated that various fatty acids, including α-linolenic acid (α-LA), inhibit URAT1; however, further investigations are required to expand our understanding for this important topic. The present study focused on certain metabolites derived from α-LA, especially jasmonates (lipid-derived cyclopentanone compounds in plants) and related substances, and investigated their effects on URAT1-mediated urate transport activity, using a mammalian cell-based functional assay system. Among the tested substances (14 authentic chemicals), 12-oxo-phytodienoic acid (a precursor of jasmonic acid harboring a cyclopentenone ring with two carbon chains in its structure) showed a good URAT1-inhibitory activity with the half maximal inhibitory concentration (IC₅₀) value of 15.9 μM. Comparable results were obtained with prostaglandin A₁ (PGA₁) and PGA₂, which are known as cyclopentenone PGs, that exhibited IC₅₀ values of 22.5 μM and 16.8 μM, respectively. Although further studies are required to address the effects of these substances on the urate regulation in humans, our findings contribute to a deeper understanding of the interactions between URAT1 and natural substances.