Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPARα-mediated redistribution of ABCB4
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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.
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Interruption of enterohepatic circulation of BAs may have therapeutic potential for attenuating cholestatic liver injury beyond their currently explored role in treatment of pruritus.
“indicating that interruption of enterohepatic circulation of BAs may have therapeutic potential for attenuating cholestatic liver injury beyond their currently explored role in treatment of pruritus.189”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [189]
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- Authors
- Shoda, J., Inada, Y., Tsuji, A., Kusama, H., Ueda, T., Ikegami, T., Suzuki, H., Sugiyama, Y., Cohen, D. E., & Tanaka, N.
- Affiliations
- University of Tsukuba (JP)
- Kissei Pharmaceutical (Japan) (JP)
- Mitsubishi Group (Japan) (JP)
- The University of Tokyo (JP)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Shoda, Junichi
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2004-10
- Volume
- 45
- Issue
- 10
- Pages
- 1813-1825
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W2087798721
- Cited by
- 58
- References
- 50
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-56626, R01DK056626, DK 48873)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- bezafibrate, ABCB4, PPARα, canalicular membrane, hepatocytes, cholestasis, cholangitis, fibrates
- MeSH terms
- Bezafibrate, Bile Canaliculi, Humans, 4-Chloro-7-nitrobenzofurazan, Phosphatidylcholines, RNA, Messenger, Tissue Distribution, ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Transporters, Hepatocytes, Cell Line, Tumor, PPAR alpha
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