Bile salt–dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4

Morita, Shin; Kobayashi, Aya; Takanezawa, Yasukazu; Kioka, Noriyuki; Handa, Tetsurou; Arai, Hiroyuki; Matsuo, Masaru; Ueda, Kazumitsu

doi:10.1002/hep.21591

Cited by 81 publications

(116 citation statements)

References 45 publications

(59 reference statements)

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“…Therefore, we hypothesized that coexpression of ABCB4 would reverse the increased PC translocation in ATP8B1-expressing cell lines. To address this hypothesis, we established cell lines stably expressing FLAG-tagged ABCB4(WT) or ABCB4(K435M), which is nonfunctional due to a mutation in the Walker A motif in the nucleotide-binding domain (41), with or without ATP8B1-HA. In both the singly and doubly expressing cell lines, comparable expression levels of ABCB4(WT) and ABCB4(K435M) were confirmed by immunoblotting, and the plasma membrane localization of all proteins was visualized by immunostaining with anti-FLAG antibody (Fig.…”

Section: L127p and I344f Mutations Abolish The Pc Flippasementioning

confidence: 99%

Phospholipid Flippase Activities and Substrate Specificities of Human Type IV P-type ATPases Localized to the Plasma Membrane

Takatsu¹,

Tanaka²,

Segawa

et al. 2014

Journal of Biological Chemistry

118

165

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Background:The enzymatic activities of mammalian P4-ATPases are incompletely characterized. Results: ATP11A and ATP11C catalyze flipping of NBD-PS and NBD-PE, whereas ATP8B1 preferentially catalyzes flipping of NBD-PC. Furthermore, some PFIC1 mutants of ATP8B1 failed to flip PC. Conclusion: ATP11A/ATP11C and ATP8B1/ATP8B2 preferentially translocate aminophospholipids and PC, respectively. Significance: This is the first evidence showing that the PC-flipping activity of ATP8B1 is associated with the episode of PFIC1.

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Section: L127p and I344f Mutations Abolish The Pc Flippasementioning

confidence: 99%

Phospholipid Flippase Activities and Substrate Specificities of Human Type IV P-type ATPases Localized to the Plasma Membrane

Takatsu¹,

Tanaka²,

Segawa

et al. 2014

Journal of Biological Chemistry

118

165

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“…26 As expected, compared with the wild type, the amount of PC secreted was reduced in both mutant-transfected cell lines. Moreover, when stably transfected cells were treated with NaTC, a molecule already documented as capable to stimulate the efflux of lipids by MDR3, 19 the data obtained showed a lower PC efflux for both mutant-transfected cell lines and similar or higher sensitivity of mutant proteins to NaTC stimulation when compared with the wild type.…”

Section: Mdr3 Dysfunction Related To Two Mutations In Nbd D Degiorgiomentioning

confidence: 75%

“…The role of the missense mutations in the pathogenesis of ABCB4-related disease remains speculative because only in a few studies 19,23,24 their pathogenicity has been correlated with direct or indirect evidence of anomalous floppase activity.…”

Section: Discussionmentioning

confidence: 99%

“…19 The canalicular MDR3 immunostaining was detectable in about 60% of the hepatocytes of the child with PFIC-3 carrying the homozygous amino-acid change from tyrosine to hystidine in the codon 403. 14 Moreover, the mutagenesis of this aromatic residue that introduces the amino acid tryptophan in the mouse Mdr1A protein did not result in a targeting-defective protein in the plasma membrane of yeast, but caused impaired ATPase transport and greatly reduced activity.…”

Section: Mdr3 Dysfunction Related To Two Mutations In Nbd D Degiorgiomentioning

confidence: 98%

“…On the basis of literature data 19 and on cell lines available in our laboratory, first experiments were performed on intrahepatic cholangiocarcinoma (HUH28), intrahepatic hepatocarcinoma (HUH7), embryonic kidney 293 (HEK293), epithelial carcinoma (HeLa), glioblastoma-astrocytoma epitheliallike (U-87MG) and endothelial capillary (EOMA) cell lines.…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

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Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction

et al. 2013

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The ABCB4 gene encodes for MDR3, a protein that translocates phosphatidylcholine from the inner to the outer leaflet of the hepatocanalicular membrane; its deficiency favors the formation of 'toxic bile'. Several forms of hepatobiliary diseases have been associated with ABCB4 mutations, but the detrimental effects of most mutations on the encoded protein needs to be clarified. Among subjects with cholangiopathies who were screened for mutations in ABCB4 by direct sequencing, we identified the new mutation p.(L481R) in three brothers. According to our model of tertiary structure, this mutation affects the Q-loop, whereas the p.(Y403H) mutation, that we already described in two other families, involves the A-loop. This study was aimed at analyzing the functional relevance of these two ABCB4 mutations: MDR3 expression and lipid content in the culture supernatant were evaluated in cell lines stably transfected with the ABCB4 wild-type clone and corresponding mutants. No differences of expression were observed between wild-type and mutant gene products. Instead, both mutations caused a reduction of phosphatidylcholine secretion compared with the wild-type transfected cell lines. On the contrary, cholesterol (Chol) release, after 1 and 3 mM sodium taurocholate stimulation, was higher in the mutant-transfected cell lines than that in the wild-type and was particularly enhanced in cells transfected with the p.Y403H-construct.In summary, our data show that both mutations do not seem to affect protein expression, but are able to reduce the efflux of phosphatidylcholine associated with increase of Chol, thereby promoting the formation of toxic bile.

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ABC Transporters in Intestinal and Liver Efflux

Morris,

Ren

2023

Oral Bioavailability and Drug Delivery

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Bile salt–dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4

Cited by 81 publications

References 45 publications

Phospholipid Flippase Activities and Substrate Specificities of Human Type IV P-type ATPases Localized to the Plasma Membrane

Phospholipid Flippase Activities and Substrate Specificities of Human Type IV P-type ATPases Localized to the Plasma Membrane

Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction

ABC Transporters in Intestinal and Liver Efflux

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