27‐Hydroxycholesterol regulates human SLC22A12 gene expression through estrogen receptor action

The excretion and reabsorption of uric acid both to and from urine are tightly regulated by uric acid transporters. Metabolic syndrome conditions, such as obesity, hypercholesterolemia, and insulin resistance, are believed to regulate the expression of uric acid transporters and decrease the excreti...

Full description

Saved in:
Bibliographic Details
Published inThe FASEB journal Vol. 35; no. 1; pp. e21262 - n/a
Main Authors Matsubayashi, Masaya, Sakaguchi, Yoshihiko M., Sahara, Yoshiki, Nanaura, Hitoki, Kikuchi, Sotaro, Asghari, Arvand, Bui, Linh, Kobashigawa, Shinko, Nakanishi, Mari, Nagata, Riko, Matsui, Takeshi K., Kashino, Genro, Hasegawa, Masatoshi, Takasawa, Shin, Eriguchi, Masahiro, Tsuruya, Kazuhiko, Nagamori, Shushi, Sugie, Kazuma, Nakagawa, Takahiko, Takasato, Minoru, Umetani, Michihisa, Mori, Eiichiro
Format Journal Article
LanguageEnglish
Published United States 01.01.2021
Subjects
27‐hydroxycholesterol
estrogen receptor
transcriptional regulatory element
uric acid
27-hydroxycholesterol
estrogen receptor
transcriptional regulatory element
uric acid
Online AccessGet full text

Cover

More Information
Summary:The excretion and reabsorption of uric acid both to and from urine are tightly regulated by uric acid transporters. Metabolic syndrome conditions, such as obesity, hypercholesterolemia, and insulin resistance, are believed to regulate the expression of uric acid transporters and decrease the excretion of uric acid. However, the mechanisms driving cholesterol impacts on uric acid transporters have been unknown. Here, we show that cholesterol metabolite 27‐hydroxycholesterol (27HC) upregulates the uric acid reabsorption transporter URAT1 encoded by SLC22A12 via estrogen receptors (ER). Transcriptional motif analysis showed that the SLC22A12 gene promoter has more estrogen response elements (EREs) than other uric acid reabsorption transporters such as SLC22A11 and SLC22A13, and 27HC‐activated SLC22A12 gene promoter via ER through EREs. Furthermore, 27HC increased SLC22A12 gene expression in human kidney organoids. Our results suggest that in hypercholesterolemic conditions, elevated levels of 27HC derived from cholesterol induce URAT1/SLC22A12 expression to increase uric acid reabsorption, and thereby, could increase serum uric acid levels.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.202002077R