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A more recent version of this article appeared on October 1, 2004

Papers In Press, published online ahead of print July 16, 2004
J. Lipid Res., doi:10.1194/jlr.M400132-JLR200
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Submitted on April 6, 2004
Revised on July 6, 2004
Accepted on July 7, 2004

Bezafibrate stimulates canalicular localization of NBD-labeled phosphatidylcholine in HepG2 cells by PPARalpha -mediated redistribution of ABCB4

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

Department of Gastroenterology, University of Tsukuba, Tsukuba-shi, Ibaraki 305-8575

Corresponding Author: shodaj{at}md.tsukuba.ac.jp

By micellization, biliary phospholipids protect against bile duct injury by hydrophobic bile acids. Decreased function of ATP binding cassette protein B4 (ABCB4), which is rate limiting for biliary phospholipid secretion, predisposes individuals to cholestasis and/or cholangitis. Fibrates, including bezafibrate (BF), up-regulate the expression of murine Abcb4, through gene transcription. 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 mu mol/L BF for 24 hours increased levels of ABCB4 mRNA but not protein 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 alpha (PPARalpha ) 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 PPARalpha -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 due to hypofunction of ABCB4.


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