**1. Introduction**

Fatty acids (FAs) are physiologically important as energy sources and membrane constituents; moreover, FAs have diverse biological activities that modulate numerous cell/tissue properties in living organisms [1]. Accumulating evidence suggests that via such actions, dietary FAs can influence human health, well-being, and the risk of disease development. For instance, intake of polyunsaturated fatty acids (PUFAs) of the ω-3 family, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been considered to reduce the risk of chronic diseases including cardiovascular diseases; however, other e ffects of FAs consumption on human health remain controversial and need further investigation [2–5]. In addition to cardiovascular diseases, it is currently acknowledged that FAs influence a range of other diseases, such as metabolic and inflammatory diseases, as well as

cancer [1]. However, little is known about the association between FAs and hyperuricemia, a common urate-related disease, especially regarding the effects of FAs on urate-handling machineries in the body.

Hyperuricemia, which is characterized by elevated serum uric acid (SUA) levels, is a lifestyle-related disease with high prevalence [6]. As hyperuricemia is a risk factor for gout, a very common form of inflammatory arthritis, SUA managemen<sup>t</sup> at appropriate levels is becoming increasingly important in daily life [7,8]. Due to the lack of functional uricase (urate-degrading enzyme) in humans [9], uric acid is the end-product of human purine metabolism; urate excretion from the body is, therefore, necessary for the maintenance of uric acid homeostasis. The kidney is responsible for elimination of approximately two-thirds of urate [10]. However, only 3%–10% of the urate filtered by the glomerulus of the kidney is secreted to the urine [11] because most of it is re-absorbed from the primary urine into the blood in the proximal tubule by the urate transporter 1 (URAT1, also known as SLC22A12)-mediated pathway [12]. Thus, inhibition of this urate re-absorption pathway contributes to SUA lowering via the increase of net renal urate excretion.

URAT1 is a physiologically important renal urate re-absorber expressed on the brush border membrane of proximal tubular cells. Among the already identified urate re-absorbers expressed on the apical side of the renal cells, URAT1 is most strongly associated with SUA levels in humans [7], as supported by the fact that *URAT1* is the causative gene for renal hypouricemia type 1 [12], an inherited disorder characterized by impaired urate re-absorption in the kidney that results in extremely low SUA levels (SUA ≤ 2 mg/dL; normal range: 3.0–7.0 mg/dL). With hyperuricemia patients, this transporter is also the pharmacological target of uricosuric agents, which promote the excretion of urate, such as benzbromarone [12], lesinurad [13], and dotinurad [14]. In this context, daily consumption of nutrients with URAT1-inhibitory activity may have a beneficial effect on SUA managemen<sup>t</sup> in subjects with high SUA levels. Actually, food ingredients that inhibit URAT1 function have attracted grea<sup>t</sup> interest; we and other groups identified some such natural ingredients from fruit flavonoids [15], coumarins [16], and wood pigments [17]. Nevertheless, despite the nutritional significance of FAs, their effects on URAT1 activity remain to be elucidated.

In the present study, we examined the URAT1-inhibitory effects of 25 FAs using an in vitro transport assay with mammalian cells transiently expressing URAT1. The cell-based assay revealed that unsaturated FAs inhibited URAT1 more strongly than saturated FAs.

#### **2. Materials and Methods**
