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Nrf2 induces fibroblast growth factor 21 in diabetic mice
Author(s) -
Furusawa Yuki,
Uruno Akira,
Yagishita Yoko,
Higashi Chika,
Yamamoto Masayuki
Publication year - 2014
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12186
Subject(s) - fgf21 , biology , gene knockdown , endocrinology , medicine , fibroblast growth factor , lipid metabolism , adipose tissue , microbiology and biotechnology , biochemistry , receptor , gene
Transcription factor N rf2 (nuclear factor E 2‐related factor 2) is a master regulator of cellular defense system against oxidative and electrophilic stresses and is negatively regulated by an adaptor protein K eap1 ( K elch‐like ECH ‐associated protein 1). Nrf2 also plays a pivotal role in metabolic homeostasis, such as lipid metabolism and energy expenditure as well as redox homeostasis. FGF 21 (fibroblast growth factor 21) is known as a key mediator of glucose and lipid metabolism. Here, we found that N rf2 is involved in FGF 21 regulation in diabetic model mice. N rf2 induction by genetic knockdown of K eap1 increased plasma FGF 21 level and hepatic F gf21 expression in diabetic db/db mice and high‐calorie‐diet‐induced obesity model mice. Administration of CDDO ‐ I m (oleanolic triterpenoid 1‐[2‐cyano‐3,12‐dioxooleane‐1, 9(11)‐dien‐28‐oyl] imidazole), a potent N rf2 inducer, up‐regulated plasma FGF 21 level and hepatic F gf21 expression in db/db mice, whereas CDDO ‐ I m did not induce FGF 21 in db/db mice with N rf2 knockout background. Furthermore, in K eap1 ‐knockdown db/db mice, N rf2 enhanced expression of glucose‐ and lipid‐metabolism‐related genes in adipose tissues, which improved plasma lipid profiles. These results show that N rf2 positively regulates FGF 21 expression in diabetic mice. We propose that FGF 21 is a potential efficacy biomarker that mediates metabolic regulation by the K eap1– N rf2 system.