TAILIEUCHUNG - Báo cáo khoa học: Hypoxia downregulates farnesoid X receptor via a hypoxia-inducible factor-independent but p38 mitogen-activated protein kinase-dependent pathway

Farnesoid X receptor (FXR), a member of the nuclear receptor superfam-ily, has been shown to play pivotal roles in bile acid homeostasis by regu-lating the biosynthesis, conjugation, secretion and absorption of bile acids. Accumulating data suggest that FXR signaling is involved in the pathogen-esis of liver and metabolic disorders. | ỊFEBS Journal Hypoxia downregulates farnesoid X receptor via a hypoxia-inducible factor-independent but p38 mitogen-activated protein kinase-dependent pathway Tomofumi Fujino1 Kaori Murakami1 Issei Ozawa1 Yoshie Minegishi1 Ryo Kashimura1 Toshihiro Akita1 Susumu Saitou1 Takehisa Atsumi1 Takashi Sato1 Ken Ando1 Shuntaro Hara2 Kiyomi Kikugawa1 and Makio Hayakawa1 1 Schoolof Pharmacy Tokyo University of Pharmacy and Life Science Japan 2 Schoolof PharmaceuticalSciences Showa University Tokyo Japan Keywords cholestasis farnesoid X receptor hypoxiainducible factor ischemia mitogen-activated protein kinase Correspondence M. Hayakawa Schoolof Pharmacy Tokyo University of Pharmacy and Life Science 1432-1 Horinouchi Hachioji Tokyo 192-0392 Japan Fax 81 42 676 4508 Tel 81 42 676 4513 E-mail hayakawa@ Received 18 September 2008 revised 28 November 2008 accepted 19 December 2008 doi Farnesoid X receptor FXR a member of the nuclear receptor superfamily has been shown to play pivotal roles in bile acid homeostasis by regulating the biosynthesis conjugation secretion and absorption of bile acids. Accumulating data suggest that FXR signaling is involved in the pathogenesis of liver and metabolic disorders. Here we show that FXR expression is significantly suppressed in HepG2 cells exposed to hypoxia. Concomitantly the expression of the bile salt export pump known as an FXR target gene product and responsible for the excretion of bile acids from the liver is also decreased under hypoxia. Overexpression of hypoxia-inducible factor HIF -1a does not mimic the suppressive effect of hypoxia on FXR expression. Furthermore simultaneous knockdown of HIF-1a HIF-2a and HIF-3a fails to restore the FXR expression level under hypoxia indicating that HIF is not involved in hypoxia-evoked FXR downregulation. Instead we demonstrate that p38 mitogen-activated protein kinase is an indispensable factor for FXR downregulation under hypoxia. Thus we propose

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