Human URAT1/ <i>SLC22A12</i> gene promoter is regulated by 27-hydroxycholesterol through estrogen response elements

<jats:title>Abstract</jats:title> <jats:p> 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/ <jats:italic>SLC22A12</jats:italic> , OAT4/ <jats:italic>SLC22A11</jats:italic> , and OAT10/ <jats:italic>SLC22A13</jats:italic> , 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/ <jats:italic>SLC22A12</jats:italic> 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/ <jats:italic>SLC22A12</jats:italic> . We also found that 27HC increased the protein and gene expression of URAT1/ <jats:italic>SLC22A12</jats:italic> in mouse kidneys and human kidney organoids, respectively. These results strongly suggest the role of 27HC for URAT1/ <jats:italic>SLC22A12</jats:italic> 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. </jats:p> <jats:sec> <jats:title>Significance Statement</jats:title> <jats:p> 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/ <jats:italic>SLC22A12</jats:italic> . We also found that URAT1/ <jats:italic>SLC22A12</jats:italic> gene promoter region has effective estrogen response elements, and endogenous selective estrogen receptor (ER) modulator 27-hydroxycholesterol (27HC) increased URAT1/ <jats:italic>SLC22A12</jats:italic> expression in the mice kidneys and human kidney organoids. These suggest that 27HC increases URAT1/ <jats:italic>SLC22A12</jats:italic> 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. </jats:p> </jats:sec>