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

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

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Identification of two functional estrogen response elements complexed with AP-1-like sites in the human insulin receptor gene promoter

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2004.12.020 ◽

2005 ◽

Vol 94 (1-3) ◽

pp. 1-14 ◽

Cited By ~ 19

Author(s):

Moisés García-Arencibia ◽

Norma Dávila ◽

Javier Campión ◽

M. Carmen Carranza ◽

Consuelo Calle

Keyword(s):

Insulin Receptor ◽

Human Insulin ◽

Receptor Gene ◽

Gene Promoter ◽

Insulin Receptor Gene ◽

Response Elements ◽

Estrogen Response ◽

Human Insulin Receptor ◽

Estrogen Response Elements

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Two functional estrogen response elements are located upstream of the major chicken vitellogenin gene.

Molecular and Cellular Biology ◽

10.1128/mcb.8.3.1123 ◽

1988 ◽

Vol 8 (3) ◽

pp. 1123-1131 ◽

Cited By ~ 55

Author(s):

J B Burch ◽

M I Evans ◽

T M Friedman ◽

P J O'Malley

Keyword(s):

Essential Feature ◽

Coding Region ◽

Transient Expression Assay ◽

Specific Expression ◽

Response Elements ◽

Estrogen Response ◽

Pair Sequence ◽

Estrogen Response Elements ◽

Vitellogenin Gene ◽

Simplex Virus

We used a transient-expression assay to identify two estrogen response elements (EREs) associated with the major chicken vitellogenin gene (VTGII). Each element was characterized by its ability to confer estrogen responsiveness when cloned in either orientation next to a chimeric reporter gene consisting of the herpes simplex virus thymidine kinase promoter and the chloramphenicol acetyl transferase-coding region. Deletion analyses indicated that sequences necessary for the distal ERE resided within the region from -626 to -613 (nucleotide positions relative to the VTGII start site) whereas those necessary for the proximal ERE were within the region from -358 to -335. These distal and proximal elements contain, respectively, a perfect copy and an imperfect copy of the 13-base-pair sequence that is an essential feature of the EREs associated with two frog vitellogenin genes. These chicken VTGII EREs mapped near regions that were restructured at the chromatin level when the endogenous VTGII gene was expressed in the liver in response to estradiol. These data suggest a model for the tissue-specific expression of this estrogen-responsive gene.

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