Omega-3 Polyunsaturated Fatty Acids Inhibit the Function of Human URAT1, a Renal Urate Re-Absorber

Abstract

The beneficial effects of fatty acids (FAs) on human health have attracted widespread interest. However, little is known about the impact of FAs on the handling of urate, the end-product of human purine metabolism, in the body. Increased serum urate levels occur in hyperuricemia, a disease that can lead to gout. In humans, urate filtered by the glomerulus of the kidney is majorly re-absorbed from primary urine into the blood via the urate transporter 1 (URAT1)-mediated pathway. URAT1 inhibition, thus, contributes to decreasing serum urate concentration by increasing net renal urate excretion. Here, we investigated the URAT1-inhibitory effects of 25 FAs that are commonly contained in foods or produced in the body. For this purpose, we conducted an in vitro transport assay using cells transiently expressing URAT1. Our results showed that unsaturated FAs, especially long-chain unsaturated FAs, inhibited URAT1 more strongly than saturated FAs. Among the tested unsaturated FAs, eicosapentaenoic acid, α-linolenic acid, and docosahexaenoic acid exhibited substantial URAT1-inhibitory activities, with half maximal inhibitory concentration values of 6.0, 14.2, and 15.2 μM, respectively. Although further studies are required to investigate whether the ω-3 polyunsaturated FAs can be employed as uricosuric agents, our findings further confirm FAs as nutritionally important substances influencing human health.

Recent Updates of Natural and Synthetic URAT1 Inhibitors and Novel Screening Methods

“…It is well established that fatty acids (FAs) influence a range of metabolic and inflammatory diseases [ 53 , 54 ] and cancer [ 55 ]. A recent study demonstrated the relationship between FAs and hyperuricemia: of 25 FAs tested in vitro [ 56 ], nine unsaturated FAs exhibited URAT1 inhibitory effects at 100 μ M, but no saturated FAs showed any effects. In particular, three long-chain unsaturated FAs exhibited strong URAT1 inhibitory effects: eicosapentaenoic acid (EPA) (compound 17) ( Figure 4 ), α -linolenic acid (ALA) (compound 18) ( Figure 4 ), and docosahexaenoic acid (DHA) (compound 19) ( Figure 4 ), which had IC 50 values of 6.0, 14.2, and 15.2 μ M, respectively.…”

“…In this model, the URAT1-expressing plasmid is transiently transfected into cells for 1-2 day protein expression, and the cells are then assayed for [ 14 C] uric acid uptake at certain time points (20 s, 5 min, 10 min) [ 21 , 76 ]. For example, for the inhibition of URAT1 by fatty acids, only 20 s of incubation is needed for uric acid uptake, which helps exclude the impact of fatty acids on the plasma membrane [ 56 ]. This method is easy, convenient, and quick.…”

Dietary and Nutritional Strategy for the Prevention and Management of Hyperuricemia

“…A study reported that consumption of fish containing omega-3 PUFA was associated with a lower propensity of recurrent gout flares. [35,36] The exact mechanism is elucidated to be as follows: inhibition of caspase-1 activation, IL-1β secretion, inhibition of NLRP3 inflammasome activation and chemotaxis. [37] Other therapies which show promise in treating gout, but require further research include guava leaves, red ginger and cocoa.…”

Soy Isoflavone Genistein Inhibits an Axillary Osmidrosis Risk Factor ABCC11: In Vitro Screening and Fractional Approach for ABCC11-Inhibitory Activities in Plant Extracts and Dietary Flavonoids

“…Human embryonic kidney 293 (HEK293)-derived 293A cells were maintained in Dulbecco's Modified Eagle's Medium (Nacalai Tesque, Kyoto, Japan) supplemented with 10% fetal bovine serum (Biowest, Nuaillé, France), 1% penicillin-streptomycin (Nacalai Tesque), 2 mM L-glutamine (Nacalai Tesque), and 1 × non-essential amino acid (Life Technologies, Tokyo, Japan) at 37 • C in a humidified atmosphere of 5% CO 2 in air (v/v), following our previous study [11]. To obtain ABCC11-expressing 293A cells for the plasma membrane vesicles, we performed plasmid transfection using polyethylenimine MAX (1 mg/mL in Milli-Q water, pH 7.0; Polysciences, Warrington, PA, USA) [12] or adenovirus infection [9], as described previously.…”