{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360568469868136192.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1101/827709"}},{"identifier":{"@type":"URI","@value":"https://syndication.highwire.org/content/doi/10.1101/827709"}}],"resourceType":"preprint","dc:title":[{"@value":"Human URAT1/\n                  <i>SLC22A12</i>\n                  gene promoter is regulated by 27-hydroxycholesterol through estrogen response elements"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Elevated levels of uric acid, a metabolite of purine in humans, is related to various diseases, such as gout, atherosclerosis and renal dysfunction. The excretion and reabsorption of uric acid to/from urine is tightly regulated by uric acid transporters. The amino acid sequences of uric acid reabsorption transporters, URAT1/\n                  <jats:italic>SLC22A12</jats:italic>\n                  , OAT4/\n                  <jats:italic>SLC22A11</jats:italic>\n                  , and OAT10/\n                  <jats:italic>SLC22A13</jats:italic>\n                  , share closer phylogenic relationship, whereas the gene promoter sequences are distant phylogenic relationship. Through the single-cell RNA-sequencing analysis of an adult human kidney, we found that only a small number of cells express these transporters, despite their role in the regulation of serum uric acid levels. Transcriptional motif analysis on these transporter genes, revealed that the URAT1/\n                  <jats:italic>SLC22A12</jats:italic>\n                  gene promoter displayed the most conserved estrogen response elements (EREs) among the three transporters. The endogenous selective estrogen receptor modulator (SERM) 27-hydroxycholesterol (27HC) had positive effects on the transcriptional activity of URAT1/\n                  <jats:italic>SLC22A12</jats:italic>\n                  . We also found that 27HC increased the protein and gene expression of URAT1/\n                  <jats:italic>SLC22A12</jats:italic>\n                  in mouse kidneys and human kidney organoids, respectively. These results strongly suggest the role of 27HC for URAT1/\n                  <jats:italic>SLC22A12</jats:italic>\n                  expression in renal proximal tubules and upregulation of serum uric acid levels and also show the relationship between cholesterol metabolism and serum uric acid regulation.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement</jats:title>\n                  <jats:p>\n                    The elevated levels of serum uric acid cause various diseases, and the excretion/reabsorption of uric acid to/from urine is tightly regulated by the uric acid transporters. We found that despite the role in serum uric acid regulation, only a small number of cells express URAT1/\n                    <jats:italic>SLC22A12</jats:italic>\n                    . We also found that URAT1/\n                    <jats:italic>SLC22A12</jats:italic>\n                    gene promoter region has effective estrogen response elements, and endogenous selective estrogen receptor (ER) modulator 27-hydroxycholesterol (27HC) increased URAT1/\n                    <jats:italic>SLC22A12</jats:italic>\n                    expression in the mice kidneys and human kidney organoids. These suggest that 27HC increases URAT1/\n                    <jats:italic>SLC22A12</jats:italic>\n                    expression and upregulate serum uric acid levels. Since 27HC connects cholesterol metabolism, our study indicates the important link between cholesterol metabolism and serum uric acid regulation, and also provides a novel therapeutic approach to hyperuricemia.\n                  </jats:p>\n                </jats:sec>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380568469868136195","@type":"Researcher","foaf:name":[{"@value":"Masaya Matsubayashi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380568469868136328","@type":"Researcher","foaf:name":[{"@value":"Yoshihiko M. Sakaguchi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380568469868136192","@type":"Researcher","foaf:name":[{"@value":"Yoshiki Sahara"}]},{"@id":"https://cir.nii.ac.jp/crid/1420845751135743744","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"00827909"},{"@type":"NRID","@value":"1000000827909"},{"@type":"NRID","@value":"9000415428787"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/Nanaura"}],"foaf:name":[{"@value":"Hitoki Nanaura"}]},{"@id":"https://cir.nii.ac.jp/crid/1380568469868136320","@type":"Researcher","foaf:name":[{"@value":"Sotaro Kikuchi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380568469868136198","@type":"Researcher","foaf:name":[{"@value":"Arvand Ashari"}]},{"@id":"https://cir.nii.ac.jp/crid/1380568469868136194","@type":"Researcher","foaf:name":[{"@value":"Linh Bui"}]},{"@id":"https://cir.nii.ac.jp/crid/1420845751154329088","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"70637628"},{"@type":"NRID","@value":"1000070637628"},{"@type":"NRID","@value":"9000017405962"},{"@type":"NRID","@value":"9000391986007"},{"@type":"NRID","@value":"9000406062858"},{"@type":"NRID","@value":"9000391987144"},{"@type":"NRID","@value":"9000347050053"},{"@type":"NRID","@value":"9000391983352"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/radiation-biology"}],"foaf:name":[{"@value":"Shinko Kobashigawa"}]},{"@id":"https://cir.nii.ac.jp/crid/1380568469868136327","@type":"Researcher","foaf:name":[{"@value":"Mari Nakanishi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380568469868136329","@type":"Researcher","foaf:name":[{"@value":"Riko Nagata"}]},{"@id":"https://cir.nii.ac.jp/crid/1380568469868136322","@type":"Researcher","foaf:name":[{"@value":"Takeshi K. 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