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27‐Hydroxycholesterol regulates human SLC22A12 gene expression through estrogen receptor action
Author(s) -
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
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202002077r
Subject(s) - uric acid , endocrinology , medicine , reabsorption , estrogen receptor , chemistry , organic anion transporter 1 , biology , transporter , kidney , biochemistry , gene , cancer , breast cancer
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.