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

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Shoda J, Inada Y, Tsuji A, Kusama H, Ueda T, Ikegami T, Suzuki H, Sugiyama Y, Cohen DE, Tanaka N

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

J Lipid Res. 2004 Oct;45(10):1813-25. Epub 2004 Jul 16.

PubMed ID

15258199 [ View in PubMed

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Abstract

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 micromol/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 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 attributable to hypofunction of ABCB4.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Phosphatidylcholine translocator ABCB4	P21439	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Bezafibrate	Approved Investigational	ABCB11	8647	downregulated	Bezafibrate results in decreased expression of ABCB11 mRNA	2q31.1
Bezafibrate	Approved Investigational	ABCB11	8647	upregulated	Bezafibrate results in increased expression of ABCB11 mRNA	2q31.1
Bezafibrate	Approved Investigational	ABCB4	5244	upregulated	Bezafibrate results in increased expression of ABCB4 mRNA	7q21.12
Bezafibrate	Approved Investigational	ABCC2	1244	upregulated	Bezafibrate results in increased expression of ABCC2 mRNA	10q24.2