ALPK1对URAT1的抑制作用与尿酸稳态相关。

URAT1 inhibition by ALPK1 is associated with uric acid homeostasis.

作者信息

Kuo Tzer-Min, Huang Chung-Ming, Tu Hung-Pin, Min-Shan Ko Albert, Wang Shu-Jung, Lee Chi-Pin, Ko Ying-Chin

机构信息

Environment-Omics-Disease Research Centre, China Medical University Hospital.

Graduate Institute of Integrated Medicine, China Medical University, Taichung.

出版信息

Rheumatology (Oxford). 2017 Apr 1;56(4):654-659. doi: 10.1093/rheumatology/kew463.

DOI:10.1093/rheumatology/kew463

PMID:28039413

Abstract

OBJECTIVE

The aim of this study was to identify a protein for urate transporter 1 (URAT1) regulation.

METHODS

The clinical dataset consisted of 492 case-control samples of Han Chinese (104 gout and 388 controls). Three alpha kinase 1 ( ALPK1 ) and SLC22A12 loci associated with high gout risk and uric acid levels were genotyped. The overexpression of ALPK1 on URAT1 protein expression was evaluated in vivo in h ALPK1 transgenic mice. The in vitro protein levels of ALPK1 and URAT1 in ALPK1 small interfering RNA-transfected human kidney-2 cells with MSU crystal stimulation were examined.

RESULTS

ALPK1 , which is a single nucleotide polymorphism (SNP) of rs11726117 (M861T; T), reduced the risk of gout via the SLC22A12 gene SNPs rs3825016 and rs475688, as compared with the subject of ALPK1 rs11726117 (C) allele {rs11726117 [CT + TT] vs rs3825016, odds ratio [OR] 0.39 [95% confidence interval (CI) 0.23, 0.67]; rs11726117 [CT + TT] vs rs475688, OR 0.39 [95% CI 0.23, 0.67]}. ALPK1-overexpressed mice demonstrated lower levels of URAT1 protein ( P = 0.0045). Mouse endogenous ALPK1 proteins were detected in renal proximal tubule cells. MSU crystals inhibited URAT1 expressions through an upregulation of ALPK1 in human kidney-2 cells.

CONCLUSION

Elevated ALPK1 expression decreased URAT1 expression. ALPK1 might prevent the impact of urate reuptake via SLC22A12 and appeared to be negatively associated with gout. ALPK1 is a potential repressor of URAT1 protein expression.

摘要

目的

本研究旨在鉴定一种参与尿酸盐转运蛋白1（URAT1）调节的蛋白质。

方法

临床数据集包含492例汉族病例对照样本（104例痛风患者和388例对照）。对与高痛风风险和尿酸水平相关的三个α激酶1（ALPK1）和溶质载体家族22成员12（SLC22A12）基因座进行基因分型。在人α激酶1转基因小鼠体内评估ALPK1过表达对URAT1蛋白表达的影响。检测在受到单钠尿酸盐（MSU）晶体刺激的情况下，经ALPK1小干扰RNA转染的人肾-2细胞中ALPK1和URAT1的体外蛋白水平。

结果

作为rs11726117（M861T；T）单核苷酸多态性的ALPK1，与携带ALPK1 rs11726117（C）等位基因的受试者相比，通过SLC22A12基因单核苷酸多态性rs3825016和rs475688降低了痛风风险{rs11726117[CT + TT]与rs3825016相比，比值比[OR]为0.39[95%置信区间（CI）0.23，0.67]；rs11726117[CT + TT]与rs475688相比，OR为0.39[95% CI 0.23，0.67]}。ALPK1过表达的小鼠表现出较低水平的URAT1蛋白（P = 0.0045）。在肾近端小管细胞中检测到小鼠内源性ALPK1蛋白。在人肾-2细胞中，MSU晶体通过上调ALPK1抑制URAT1表达。