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Journal of Lipid Research, Vol. 45, 1813-1825, October 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPAR-mediated redistribution of ABCB4

Junichi Shoda^1,2,*, Yoichi Inada^1,, Atsutoshi Tsuji, Hiroshi Kusama, Tetsuya Ueda, Tadashi Ikegami^*, Hiroshi Suzuki^**, Yuichi Sugiyama^**, David E. Cohen and Naomi Tanaka^*

^* Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Pharmacology Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Kashiwabara, Hotaka, Minamiazumi, Nagano 399-8304, Japan
Department of Pharmaceutical Research, Mitsubishi Kagaku Bio-Clinical Laboratories, Inc., 3-30-1 Shimura, Itabashi-ku, Tokyo 174-0056, Japan
^** Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Departments of Medicine and Biochemistry, Marion Bessin Liver Research Center, Ullmann 625, Albert Einstein College of Medicine, Bronx, NY 10461

² To whom correspondence should be addressed. e-mail: shodaj{at}md.tsukuba.ac.jp

Fibrates, including bezafibrate (BF), upregulate the expression of ATP binding cassette protein B4 (ABCB4) through gene transcription in mice. To determine the effects of BF on the expression levels of ABCB4 and on the stimulation of biliary phosphatidylcholine (PC) transport in human HepG2 hepatoblastoma cells, mRNA and protein levels as well as subcellular localization were investigated in the cells treated with BF. The canalicular accumulation of a fluorescent PC was assessed by confocal laser scanning microscopy. Treatment with 300 µmol/l BF for 24 h increased levels of ABCB4 mRNA but not protein by up to 151%. BF caused redistribution of ABCB4 into pseudocanaliculi formed between cells. In association with this redistribution, BF accelerated the accumulation of fluorescent PC in bile canaliculi (up to 163% of that in nontreated cells). Suppression of peroxisome proliferator-activated receptor (PPAR) expression by either a small interfering RNA duplex or morpholino antisense oligonucleotide attenuated the BF-induced redistribution of ABCB4.

These findings suggest that BF may enhance the capacity of human hepatocytes to direct PC into bile canaliculi via PPAR-mediated redistribution of ABCB4 to the canalicular membrane. This provides a rationale for the use of BF to improve cholestasis and/or cholangitis that is attributable to hypofunction of ABCB4.

Abbreviations: ABC, ATP binding cassette protein; BF, bezafibrate; CD26, cluster of differentiation 26; CLSM, confocal laser scanning microscopy; C6-NBD-PC, nitrobenzoxadiaole-labeled 1-palmitoyl-2-[6-[(7-nitro-2-1,3-benzoxadiazol-4-y)amino]caproyl]-sn-glycero-3-phosphatidylcholine; PAb, polyclonal antibody; PC, phosphatidylcholine; PCTP, phosphatidylcholine transfer protein; PPAR, peroxisome proliferator-activated receptor ; siRNA, small interfering RNA

Supplementary key words ATP binding cassette protein B4 • human hepatocyte • multidrug-resistance 3 P-glycoprotein • subcellular localization • functional activity • nuclear hormone receptor • phosphatidylcholine • peroxisome proliferator-activated receptor • nitrobenzoxadiazole

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