title: URAT1 inhibition by ALPK1 is associated with uric acid homeostasis.
abstract: The aim of this study was to identify a protein for urate transporter 1 (URAT1) regulation.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Environment-Omics-Disease Research Centre, China Medical University Hospital.
authors.forename: Tzer-Min
authors.initials: TM
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Integrated Medicine, China Medical University, Taichung.
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Huang
authors.affiliation: Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hung-Pin
authors.initials: HP
authors.lastname: Tu
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Min-Shan Ko
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung.
authors.forename: Shu-Jung
authors.initials: SJ
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung.
authors.forename: Chi-Pin
authors.initials: CP
authors.lastname: Lee
authors.affiliation: Environment-Omics-Disease Research Centre, China Medical University Hospital.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Ying-Chin
authors.initials: YC
authors.lastname: Ko
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D003460:Crystallization; D006073:Gout / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000494:pharmacology*; D015854:Up-Regulation / Q000502:physiology; D014527:Uric Acid / Q000378:metabolism*
chemical_list: D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C109687:Slc22a12 protein, mouse; D014527:Uric Acid; C000604235:ALPK1 protein, mouse; D011494:Protein Kinases
keywords: ALPK1; MSU; URAT1; gout; hyperuricaemia