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

URAT1 inhibition by ALPK1 is associated with uric acid homeostasis.

Author information

1
Environment-Omics-Disease Research Centre, China Medical University Hospital.
2
Graduate Institute of Integrated Medicine, China Medical University, Taichung.
3
Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
4
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
5
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung.
6
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.

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.

KEYWORDS:

ALPK1; MSU; URAT1; gout; hyperuricaemia

PMID:
28039413
DOI:
10.1093/rheumatology/kew463
[Indexed for MEDLINE]

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