Tài liệu Báo cáo khoa học: Hypoxia downregulates farnesoid X receptor via a hypoxia-inducible

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 School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan

2 School of Pharmaceutical Sciences, Showa University, Tokyo, Japan

Nuclear receptors (NRs) are ligand-activated transcrip￾tional factors that belong to a large superfamily

consisting of over 150 different members [1]. Farne￾soid X receptor (FXR), a member of the NR super￾family, was first isolated from a rat liver cDNA

library, and named after its weak activation by supra￾physiological concentrations of farnesol, an intermedi￾ate in the mevalonate biosynthetic pathway [2].

Subsequent studies have revealed that certain types of

bile acids act as physiological ligands for FXR, leading

to its activation [3–5].

FXR expression is limited to very few tissues; it is

highly expressed in the liver, intestine, kidney, and

adrenal gland [2,6–8], whereas lower levels of expres￾sion are reported in adipose tissues and heart [9–11].

FXR forms a heterodimer with retinoid X receptor

Keywords

cholestasis; farnesoid X receptor; hypoxia￾inducible factor; ischemia; mitogen-activated

protein kinase

Correspondence

M. Hayakawa, School of 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: [email protected]

(Received 18 September 2008, revised 28

November 2008, accepted 19 December

2008)

doi:10.1111/j.1742-4658.2009.06867.x

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. 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 expres￾sion. 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 indispens￾able factor for FXR downregulation under hypoxia. Thus, we propose a

novel liver disorder model in which two signaling molecules, p38 mitogen￾activated protein kinase and FXR, may contribute to the linkage of two

pathogenic conditions, i.e. ischemia, a condition accompanying hypoxia,

and cholestasis, a condition with intrahepatic accumulation of cytotoxic

bile acids.

Abbreviations

BSEP, bile salt export pump; CDCA, chenodeoxycholic acid; ERK, extracellular signal-regulated kinase; FXR, farnesoid X receptor; FXRE,

farnesoid X receptor response element; GLUT-1, glucose transporter-1; HCC, hepatocellular carcinoma; HIF, hypoxia-inducible factor; IL,

interleukin; JNK, c-Jun N-terminal kinase; LRH-1, liver receptor homolog 1; MAPK, mitogen-activated protein kinase; MRP, multidrug

resistant-associated protein; NF-jB, nuclear factor kappaB; NR, nuclear receptor; SD, standard deviation; SHP, small heterodimer partner;

siRNA, small interfering RNA; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

FEBS Journal 276 (2009) 1319–1332 ª 2009 The Authors Journal compilation ª 2009 FEBS 1319