Frontier Laboratories for Value Creation, SAPPORO HOLDINGS LTD, 10 Okatome, Yaizu, Shizuoka, 425-0013, Japan; Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Centre Research Institute, 6-1 Kishibe-Shinmachi, Suita, Osaka, 564-8565, Japan.
Frontier Laboratories for Value Creation, SAPPORO HOLDINGS LTD, 10 Okatome, Yaizu, Shizuoka, 425-0013, Japan.
Biochem Biophys Res Commun. 2020 Jan 22;521(4):861-867. doi: 10.1016/j.bbrc.2019.10.199. Epub 2019 Nov 8.
Hyperuricemia is caused by hepatic overproduction of uric acid and/or underexcretion of urate from the kidneys and small intestine. Although increased intake of citrus fruits, a fructose-rich food, is associated with increased risk of gout in humans, hesperidin, a flavonoid naturally present in citrus fruits, reportedly reduces serum uric acid (SUA) levels by inhibiting xanthine oxidase (XOD) activity in rats. However, the effects of hesperidin on renal and intestinal urate excretion were previously unknown. In this study, we used glucosyl hesperidin (GH), which has greater bioavailability than hesperidin, to clarify comprehensive mechanisms underlying the hypouricemic effects of hesperidin in vivo. GH dose-dependently decreased SUA levels in mice with hyperuricemia induced by potassium oxonate and a fructose-rich diet, and inhibited XOD activity in the liver. GH decreased renal urate excretion without changes in kidney URAT1, ABCG2 or GLUT9 expressions, suggesting that reducing uric acid pool size by inhibiting XOD decreased renal urate excretion. We also found that GH had no effect on intestinal urate excretion or protein expression of ABCG2. Therefore, we concluded that GH exhibits a hypouricemic effect by inhibiting XOD activity in the liver without increasing renal or intestinal urate excretion. Of note, this is the first study to elucidate the effect of a flavonoid on intestinal urate excretion using a mice model, whose findings should prove useful in future food science research in the area of urate metabolism. Taking these findings together, GH may be useful for preventing hyperuricemia, especially in people with the overproduction type.
高尿酸血症是由肝脏尿酸生成过多和/或肾脏和小肠尿酸排泄减少引起的。尽管增加柑橘类水果（一种富含果糖的食物）的摄入与人类痛风风险增加有关，但柚皮苷，一种天然存在于柑橘类水果中的类黄酮，据报道可通过抑制黄嘌呤氧化酶（XOD）活性来降低血清尿酸（SUA）水平。然而，柚皮苷对肾脏和肠道尿酸排泄的影响以前尚不清楚。在这项研究中，我们使用了葡萄糖基柚皮苷（GH），它比柚皮苷具有更高的生物利用度，以阐明柚皮苷在体内降尿酸作用的综合机制。GH 剂量依赖性地降低了由氧嗪酸钾和富含果糖的饮食诱导的高尿酸血症小鼠的 SUA 水平，并抑制了肝脏中的 XOD 活性。GH 降低了肾脏尿酸排泄，而肾脏 URAT1、ABCG2 或 GLUT9 的表达没有变化，这表明通过抑制 XOD 减少尿酸库大小会降低肾脏尿酸排泄。我们还发现 GH 对肠道尿酸排泄或 ABCG2 的蛋白表达没有影响。因此，我们得出结论，GH 通过抑制肝脏中的 XOD 活性而不增加肾脏或肠道尿酸排泄来发挥降尿酸作用。值得注意的是，这是第一项使用小鼠模型阐明类黄酮对肠道尿酸排泄影响的研究，其研究结果在未来尿酸代谢领域的食品科学研究中应该是有用的。综上所述，GH 通过抑制肝脏中的 XOD 活性而不增加肾脏或肠道尿酸排泄来发挥降尿酸作用，这可能对预防高尿酸血症，特别是对尿酸生成过多型的人有用。
