Affinage

ABCB4

Phosphatidylcholine translocator ABCB4 · UniProt P21439

Length
1286 aa
Mass
141.5 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ABCB4 (MDR3) is the ATP-dependent phosphatidylcholine translocator of the hepatocyte bile canalicular membrane and is essential for biliary phospholipid secretion (PMID:8106172, PMID:7734012, PMID:1673638). Genetic dose-response studies show that biliary phospholipid output is entirely and quantitatively dependent on ABCB4/Mdr2 expression level, making it the rate-limiting step in phospholipid translocation, whereas cholesterol can be partially secreted by an ABCB4-independent route (PMID:7814632, PMID:8725158). Human MDR3 is functionally homologous to murine Mdr2 and fully restores biliary phosphatidylcholine excretion when expressed in Mdr2-deficient hepatocytes (PMID:9696021); unlike its MDR1 paralog, MDR3 does not transport classical multidrug-resistance substrates (PMID:7734012, PMID:1673638). Purified ABCB4 displays phosphatidylcholine-inducible ATPase activity, providing direct biochemical evidence that PC is its transport substrate (PMID:23593265). ABCB4 acts upstream of ABCG5/G8-mediated biliary cholesterol secretion, which is epistatically dependent on functional Mdr2 (PMID:15930516). Its transcription is directly activated by FXR through an inverted-repeat response element in the distal promoter (PMID:14527955), by PPARα in response to fibrates (PMID:12381268), and by thyroid hormone receptor β1 via upstream response elements (PMID:29895698); the gene's promoter lacks TATA/CAAT boxes and is SP1-dependent (PMID:7893760). ABCB4 is additionally regulated post-translationally by phosphorylation of its N-terminal domain (including T34) by protein kinases A and C, which enhances PC secretion activity (PMID:24723470). Loss-of-function mutations cause progressive familial intrahepatic cholestasis type 3 (PFIC3), with disease severity and UDCA responsiveness tracking the degree of residual floppase activity (PMID:9419367, PMID:24594635); distinct mutation classes act by abrogating expression, disrupting trafficking, or impairing the nucleotide-binding domain (PMID:10767346, PMID:24045840), and trafficking-defective mutants can be rescued by chemical chaperones or by lipid-nanoparticle delivery of synthetic ABCB4 mRNA (PMID:26900700, PMID:33340584).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1993 High

    Establishing that the Mdr2/ABCB4 P-glycoprotein is required for a specific physiological process — biliary phospholipid secretion — rather than drug efflux, which had been unknown for this MDR family member.

    Evidence Homozygous mdr2 knockout mice with biliary lipid analysis

    PMID:8106172

    Open questions at the time
    • Did not establish whether the protein acts directly as a phospholipid translocator or indirectly
    • Human ortholog function not yet tested
  2. 1994 High

    Localized human MDR3 to the bile canalicular membrane and showed it does not confer drug resistance, distinguishing it functionally from MDR1 and tying it to canalicular transport.

    Evidence MDR3-specific antibody immunocytochemistry and transfection drug-resistance assays in melanoma cells

    PMID:1673638 PMID:7734012

    Open questions at the time
    • Direct substrate not identified
    • Mechanism of phospholipid handling unresolved
  3. 1995 High

    Quantified the rate-limiting role of Mdr2 by showing gene-dosage-dependent phospholipid output and uncoupling of phospholipid from cholesterol secretion.

    Evidence Bile duct cannulation and lipid analysis across three mdr2 genotypes at varying bile salt infusion rates

    PMID:7814632 PMID:8725158

    Open questions at the time
    • Molecular basis of mdr2-independent cholesterol secretion not defined
  4. 1998 High

    Demonstrated functional equivalence of human MDR3 and murine Mdr2 in vivo and linked human MDR3 loss-of-function mutations to PFIC3, defining the disease gene.

    Evidence Hepatocyte-specific human MDR3 transgenic rescue of Mdr2-/- mice; mutation analysis and IHC in PFIC3 patients

    PMID:9419367 PMID:9696021

    Open questions at the time
    • Genotype–phenotype relationship for missense variants not yet quantified
    • Biochemical transport mechanism still inferred
  5. 2000 Medium

    Introduced a mechanistic mutation class — trafficking defects — by showing an ICP-associated missense change blocks cell-surface delivery.

    Evidence Site-directed mutagenesis modeled in MDR1 surrogate; FACS and western analysis of surface expression

    PMID:10767346

    Open questions at the time
    • Used MDR1 surrogate rather than MDR3 itself
    • Single lab, no in vivo confirmation
  6. 2003 High

    Identified direct transcriptional control of ABCB4 by FXR and PPARα, connecting bile-acid and lipid signaling to phospholipid transporter expression.

    Evidence Promoter reporter mutagenesis and FXR trans-activation in primary human hepatocytes; PPARα knockout mice with fibrate treatment

    PMID:12381268 PMID:14527955

    Open questions at the time
    • Interplay between these regulators not dissected
    • Quantitative contribution to in vivo flux unclear
  7. 2013 High

    Provided the first direct biochemical proof that phosphatidylcholine is the ABCB4 substrate by reconstituting substrate-inducible ATPase activity.

    Evidence Pichia pastoris expression, purification, and ATPase assay with phosphatidylcholine

    PMID:23593265

    Open questions at the time
    • No reconstituted vectorial flipping assay
    • No structural model of the transport cycle
  8. 2014 High

    Resolved how distinct mutation classes impair function and established that residual floppase activity quantitatively predicts PFIC3 severity and UDCA response, plus added post-translational (phosphorylation) regulation of activity.

    Evidence PC efflux assays, localization, and immunoblotting of ABCB4 missense and NBD-motif mutants; mass spectrometry and kinase modulation of the N-terminal domain

    PMID:24045840 PMID:24594635 PMID:24723470

    Open questions at the time
    • Kinase identities at canalicular membrane in vivo not pinned down
    • Structural consequences of NBD mutations not solved
  9. 2016 High

    Showed that ER-retained trafficking mutants are pharmacologically correctable, opening a therapeutic strategy through improved maturation.

    Evidence Chemical chaperone (4-PBA, curcumin) rescue with localization, maturation, and PC efflux assays in transfected cells

    PMID:26900700

    Open questions at the time
    • In vivo efficacy not tested
    • Mutation-class generality unknown
  10. 2018 Medium

    Extended transcriptional regulation to thyroid hormone receptor β1, identifying another inducible axis with in vivo biliary effects.

    Evidence Promoter analysis and THRβ1-specific agonist treatment in hepatocyte models and mice with biliary PC measurement

    PMID:29895698

    Open questions at the time
    • Single lab
    • Physiological relevance versus pharmacological induction unclear
  11. 2020 High

    Demonstrated that restoring ABCB4 protein via synthetic mRNA delivery rescues the phospholipid-secretion defect in vivo, validating replacement therapy.

    Evidence LNP-delivered human ABCB4 mRNA in PFIC3 model cells and Abcb4-/- mice with functional and histological readouts

    PMID:33340584

    Open questions at the time
    • Durability and dosing in chronic disease not established
  12. 2024 Medium

    Identified a non-hepatic, oncogenic context in which ATF3-driven ABCB4 confers and propagates drug resistance via exosomes in glioblastoma stem cells.

    Evidence Luciferase and ChIP-qPCR for ATF3 binding; exosome transfer and TMZ resistance assays in vitro and in vivo

    PMID:38710703

    Open questions at the time
    • Substrate handled in glioma context not defined
    • Mechanism of resistance transfer beyond ABCB4 presence unclear
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ABCB4 mechanically couples ATP hydrolysis to vectorial phosphatidylcholine flipping and extraction into bile at atomic resolution remains unresolved.
  • No structure of the transport cycle
  • Stoichiometry of ATP use per lipid flipped unknown
  • In vivo regulatory kinase identities not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0008289 lipid binding 3 GO:0016787 hydrolase activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-382551 Transport of small molecules 3 R-HSA-1430728 Metabolism 2
Partners
FXRPPARARXRATHRB

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Homozygous disruption of the murine mdr2 gene leads to complete absence of phospholipid (phosphatidylcholine) from bile and liver disease, establishing that mdr2 P-glycoprotein (ortholog of human ABCB4/MDR3) is essential for phosphatidylcholine secretion into bile. Gene knockout mouse model (mdr2-/- mice); biliary lipid analysis Cell High 8106172
1994 Human MDR3 P-glycoprotein localizes specifically to the bile canalicular membrane of hepatocytes (not bile ductule epithelium), consistent with its role in phospholipid transport into bile; MDR3 expression does not confer drug resistance when transfected into drug-sensitive cells. Immunocytochemistry and immunoblotting with MDR3-specific polyclonal antibodies; stable transfection into BRO melanoma cells with drug resistance assays Laboratory investigation; a journal of technical methods and pathology High 1673638 7734012
1991 Human MDR3 P-glycoprotein expressed in transfected cells localizes mainly to the plasma membrane and is likely glycosylated, but does not transport a range of multidrug-resistance substrates (vincristine, colchicine, VP16, daunorubicin, doxorubicin, actinomycin D, gramicidin D) and does not enhance daunorubicin efflux. Stable transfection of MDR3 cDNA into BRO melanoma cells; immunocytochemistry; immunoblotting; fluorescence microscopy drug efflux; drug resistance assays Cancer research High 1673638
1995 Biliary phospholipid secretion is entirely dependent on mdr2 P-glycoprotein expression level (mdr2+/- mice have half-normal phospholipid output), establishing a quantitative, rate-limiting role for mdr2/ABCB4 in phospholipid translocation; cholesterol can be partially secreted via an mdr2-independent mechanism. Bile duct cannulation and lipid analysis in mdr2 +/+, +/-, and -/- mice at various bile salt infusion rates The Journal of clinical investigation High 7814632
1998 Human MDR3 P-glycoprotein is functionally homologous to murine Mdr2 and can fully rescue biliary phosphatidylcholine excretion in Mdr2-/- mice when expressed specifically in hepatocytes under an albumin promoter; phospholipid excretion correlates quantitatively with MDR3/Mdr2 protein levels. Transgenic mouse rescue experiment: hepatocyte-specific expression of human MDR3 in Mdr2-/- mice; biliary lipid analysis; immunohistochemistry Hepatology (Baltimore, Md.) High 9696021
1998 Loss-of-function mutations in the human MDR3 gene (a 7-bp deletion causing frameshift/stop codon, and a nonsense mutation at codon 957) cause progressive familial intrahepatic cholestasis type 3 (PFIC3) with absent canalicular MDR3 staining, establishing that MDR3 is the human phosphatidylcholine translocator whose deficiency causes PFIC3. Immunohistochemistry for MDR3 protein; RT-PCR sequencing; genomic DNA analysis in PFIC3 patients Proceedings of the National Academy of Sciences of the United States of America High 9419367
2000 A heterozygous missense mutation in MDR3 (A546D in codon 546, exon 14) associated with intrahepatic cholestasis of pregnancy causes disruption of protein trafficking with lack of functional protein at the cell surface, demonstrated by introducing the equivalent mutation into MDR1 and assaying by FACS and western analysis. Site-directed mutagenesis introduced into MDR1 (MDR3 homolog); FACS; western blot analysis of cell-surface protein expression Human molecular genetics Medium 10767346
2003 MDR3/ABCB4 gene transcription is directly activated by the nuclear receptor FXR (farnesoid X receptor) via binding of FXR/RXRα heterodimers to a conserved inverted repeat element (FXR response element) at position -1970 to -1958 in the MDR3 distal promoter; both endogenous (chenodeoxycholate) and synthetic (GW4064) FXR agonists induce MDR3 mRNA in primary human hepatocytes. Luciferase reporter assays; deletion/mutation of FXR response element; FXR trans-activation assays; RT-PCR in primary human hepatocytes The Journal of biological chemistry High 14527955
2003 PPARα mediates fibrate-induced transcriptional upregulation of hepatic Mdr2 (Abcb4) expression and Mdr2 protein levels; fibrate effects on Mdr2 were absent in PPARα-/- mice, and PPARα agonists specifically induced Mdr2 mRNA in cultured wild-type hepatocytes. PPARα knockout mice; ciprofibrate diet treatment; Northern blot; immunoblotting; isolated hepatocyte cultures with PPARα agonists The Biochemical journal High 12381268
2014 The N-terminal domain of ABCB4 undergoes phosphorylation (at residues including T34 and nearby sites), and disease-associated mutations T34M and R47G impair this phosphorylation and markedly decrease phosphatidylcholine (PC) secretion activity without affecting protein maturation or apical membrane targeting; pharmacological activation of protein kinases A or C increases ABCB4-mediated PC secretion. Mass spectrometry of N-terminal domain; site-directed mutagenesis; in vitro phosphorylation assay; PC secretion assays in polarized MDCK and HepG2 cells; protein kinase modulators Hepatology (Baltimore, Md.) High 24723470
2014 The degree of MDR3 (ABCB4) floppase activity correlates directly with PFIC3 clinical outcomes: ABCB4 missense mutations cause variable reductions in phosphatidylcholine-translocating activity (measured by PC efflux assay), and mutations causing total loss of MDR3 expression/function result in progressive disease refractory to UDCA, while residual activity of ~33–50% allows favorable UDCA response. In vitro PC efflux assays; subcellular localization by immunofluorescence; immunoblotting of MDR3 expression; ABCB4 sequencing in PFIC3 patients Gut High 24594635
2014 Two ABCB4 mutations affecting nucleotide-binding domain motifs (p.L481R affecting Q-loop; p.Y403H affecting A-loop) do not prevent protein expression or targeting to plasma membrane, but both reduce phosphatidylcholine secretion; the p.Y403H mutant also causes increased cholesterol release upon bile salt stimulation. Stable transfection of wild-type and mutant ABCB4 into cell lines; PC and cholesterol measurement in culture supernatant; immunoblotting European journal of human genetics : EJHG Medium 24045840
2016 ABCB4 trafficking-defective mutants (G228R and A934T), which are retained in the endoplasmic reticulum, can be functionally rescued by chemical chaperones 4-phenylbutyrate (4-PBA) or curcumin: these compounds restore cell-surface expression via improved maturation rate (not stabilization of mature form) and rescue bile salt-dependent phospholipid efflux activity. Transfected MDCK-II and AD-293 cells; confocal immunofluorescence for subcellular localization; immunoblotting for maturation; PC efflux activity assay; reduced temperature rescue PloS one High 26900700
2013 Human MDR3 (ABCB4) can be expressed and purified from Pichia pastoris; the purified protein displays substrate-inducible ATPase activity upon addition of phosphatidylcholine lipids, providing biochemical evidence that PC is a substrate for the ABCB4 ATPase. Heterologous expression in Pichia pastoris; protein purification; fluorescence-detection size-exclusion chromatography; ATPase activity assay with phosphatidylcholine PloS one High 23593265
2005 ABCG5/ABCG8-mediated biliary cholesterol secretion requires MDR2/ABCB4 expression: in Mdr2-/-;hG5G8Tg mice, overexpression of ABCG5/G8 cannot restore biliary cholesterol levels, demonstrating epistatic dependence of ABCG5/G8 sterol secretion on functional Mdr2. Double-transgenic/knockout mice (Mdr2-/- crossed with hG5G8Tg); biliary lipid analysis; fractional sterol absorption measurement Journal of lipid research High 15930516
1999 Statins (simvastatin, pravastatin) induce hepatic mdr2 mRNA and protein expression in rats, leading to increased biliary phospholipid and cholesterol secretion; induction is most pronounced in periportal hepatocytes. Rat dietary statin treatment; Northern blot; immunoblotting; immunohistochemistry; biliary lipid analysis Gastroenterology Medium 10464145
1997 Peroxisome proliferators (phenoxyacetic acid herbicides, plasticizers, partially hydrogenated fish oil) induce mdr2 gene expression at the transcriptional level (confirmed by nuclear run-off assay), increase Mdr2 P-glycoprotein in hepatocyte canalicular membrane, and enhance biliary phospholipid output in mice. Northern blot; nuclear run-off transcription assay; immunohistochemistry; biliary phospholipid measurement in treated mice Journal of hepatology Medium 9210621
2018 Thyroid hormone receptor β1 (THRβ1) directly activates ABCB4 transcription via conserved THR response elements ~6 kb upstream of the ABCB4 locus; THRβ1-specific agonists increase hepatic ABCB4 expression in mice and enhance biliary PC secretion in vivo. Promoter analysis; THRβ1-specific agonist treatment (GC-1, KB-141) in human hepatocyte models and mice; in vivo biliary PC measurement Journal of lipid research Medium 29895698
1998 Biliary secretion of alpha-tocopherol is partly dependent on functional mdr2 P-glycoprotein: mdr2 knockout mice have ~25% of wild-type biliary alpha-tocopherol levels, and the P-glycoprotein inhibitor verapamil prevents PIP-induced increases in biliary alpha-tocopherol and phosphatidylcholine output in rats. mdr2 knockout mice; verapamil inhibition experiments in rats; biliary lipid and alpha-tocopherol measurement Archives of biochemistry and biophysics Medium 9473291
1996 Biliary phospholipid secretion completely depends on mdr2 gene expression, while cholesterol can be partially secreted via an mdr2-independent mechanism whose extent depends on bile salt hydrophobicity; these pathways can be uncoupled. Bile infusion with taurodeoxycholate and tauroursodeoxycholate in mdr2 +/+, +/-, -/- mice; biliary lipid analysis Journal of lipid research High 8725158
2020 Synthetic human ABCB4 mRNA delivered via lipid nanoparticles to hepatocytes results in de novo functional ABCB4 protein expression and restores phospholipid transport in PFIC3 model cells and Abcb4-/- mouse livers, rescuing the disease phenotype. LNP-encapsulated hABCB4 mRNA; cell-based phospholipid transport assay; in vivo treatment of BALB/c.Abcb4-/- mice; liver histology and biochemistry Journal of hepatology High 33340584
2014 In Abcb4-/- mice, canalicular transporters BSEP (Abcb11), MRP2, and ATP8B1 are secondarily reduced at the protein level while ABCG5/G8 are increased; ATP8B1 loses normal apical membrane localization by 12 weeks; these compensatory changes begin before overt histological injury and may contribute to cholestasis pathogenesis. Immunofluorescence localization; immunoblotting; RT-PCR across developmental timepoints in Abcb4-/- mice American journal of physiology. Gastrointestinal and liver physiology Medium 24481602
1999 Mdr2 P-glycoprotein deficiency in mice causes posttranscriptional downregulation of the sinusoidal bile acid uptake transporter Ntcp (4–6-fold reduction in protein, unchanged mRNA), resulting in 2-fold reduced Vmax of Na+-dependent taurocholate uptake; this accounts for elevated plasma bile salt levels in mdr2-/- mice. Plasma membrane isolation; Na+-dependent taurocholate transport kinetics; Western blotting; Northern blot and RT-PCR for Ntcp mRNA Journal of hepatology Medium 9927146
2024 In glioblastoma stem cells (GSCs), the transcription factor ATF3 directly drives ABCB4 transcription (confirmed by luciferase assay and ChIP-qPCR); ABCB4 promotes GSC resistance to temozolomide, and ABCB4-containing exosomes secreted by GSCs transfer this resistance to differentiated glioma cells. Luciferase reporter assay; chromatin immunoprecipitation-qPCR; exosome isolation by ultracentrifugation; in vitro and in vivo TMZ resistance assays Cell death & disease Medium 38710703
1995 The human MDR3 promoter lacks TATA and CAAT boxes but contains multiple SP1 binding sites; a 3 kb genomic fragment containing multiple transcription start sites directs orientation-dependent, SV40 enhancer-stimulated transcription of a CAT reporter in HepG2 hepatoma cells. Promoter cloning; CAT reporter transfection; RNase protection; primer extension Biochimica et biophysica acta Medium 7893760

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 1267 8106172
1998 Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proceedings of the National Academy of Sciences of the United States of America 541 9419367
1994 Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. The American journal of pathology 314 7977654
1987 The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver. The EMBO journal 277 2892668
1988 Sequence of mdr3 cDNA encoding a human P-glycoprotein. Gene 267 2906314
2001 MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology 250 11313316
1991 Characterization of the human MDR3 P-glycoprotein and its recognition by P-glycoprotein-specific monoclonal antibodies. Cancer research 222 1673638
2005 Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. Journal of hepatology 217 16223543
1990 Expression of mdr1 and mdr3 multidrug-resistance genes in human acute and chronic leukemias and association with stimulation of drug accumulation by cyclosporine. Journal of the National Cancer Institute 216 1972761
2000 Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Human molecular genetics 214 10767346
2004 Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 209 15077010
2003 ABCB4 gene mutation-associated cholelithiasis in adults. Gastroenterology 207 12891548
2006 Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Archiv : European journal of physiology 204 16622704
1995 Regulation of biliary lipid secretion by mdr2 P-glycoprotein in the mouse. The Journal of clinical investigation 194 7814632
2011 Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO⁻₃ output. Hepatology (Baltimore, Md.) 189 22006858
2010 The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Seminars in liver disease 181 20422496
2003 Farnesoid X receptor activates transcription of the phospholipid pump MDR3. The Journal of biological chemistry 178 14527955
2007 MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Seminars in liver disease 163 17295178
2004 Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells. Molecular cancer therapeutics 145 15252144
1996 Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene. Gastroenterology 144 8698195
1994 Tissue distribution of the human MDR3 P-glycoprotein. Laboratory investigation; a journal of technical methods and pathology 142 7734012
2003 Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. The Biochemical journal 136 12381268
2008 ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults. Gastroenterology 131 18482588
2004 Spontaneous cholecysto- and hepatolithiasis in Mdr2-/- mice: a model for low phospholipid-associated cholelithiasis. Hepatology (Baltimore, Md.) 129 14752830
2004 BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology (Baltimore, Md.) 129 14999697
1997 Hepatic canalicular membrane 1: The role of mdr2 P-glycoprotein in hepatobiliary lipid transport. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 121 9034162
2017 Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2-/- ) mice. Hepatology (Baltimore, Md.) 116 28802066
2007 Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene. Orphanet journal of rare diseases 106 17562004
1991 Structure of the human MDR3 gene and physical mapping of the human MDR locus. The Journal of biological chemistry 106 2002063
2019 Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice. Journal of hepatology 105 31071368
1998 Hepatocyte-specific expression of the human MDR3 P-glycoprotein gene restores the biliary phosphatidylcholine excretion absent in Mdr2 (-/-) mice. Hepatology (Baltimore, Md.) 105 9696021
2017 Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. Journal of hepatology 102 28733223
2008 Tissue distribution, gender-divergent expression, ontogeny, and chemical induction of multidrug resistance transporter genes (Mdr1a, Mdr1b, Mdr2) in mice. Drug metabolism and disposition: the biological fate of chemicals 94 18854377
1990 Overexpression of the multidrug resistance gene mdr3 in spontaneous and chemically induced mouse hepatocellular carcinomas. Molecular and cellular biology 92 2122232
2006 Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11). Drug metabolism and disposition: the biological fate of chemicals 80 16763017
2020 Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. Journal of hepatology 79 32376413
1993 Cloning and regulation of the rat mdr2 gene. Nucleic acids research 79 8103593
2005 ABCG5 and ABCG8 require MDR2 for secretion of cholesterol into bile. Journal of lipid research 75 15930516
1996 Uncoupling of biliary phospholipid and cholesterol secretion in mice with reduced expression of mdr2 P-glycoprotein. Journal of lipid research 73 8725158
2000 Effects of MDR1 and MDR3 P-glycoproteins, MRP1, and BCRP/MXR/ABCP on the transport of (99m)Tc-tetrofosmin. Biochemical pharmacology 71 10856437
2014 Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity. Gut 67 24594635
2007 Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Hepatology (Baltimore, Md.) 65 17187437
2018 ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum. Seminars in liver disease 62 30357767
2007 Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 60 18083082
1990 Expression of the mdr3 gene in prolymphocytic leukemia: association with cyclosporin-A-induced increase in drug accumulation. International journal of cancer 60 2323839
2020 Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4-/- mouse model of PFIC3. Journal of hepatology 59 33340584
2018 Blocking H1/H2 histamine receptors inhibits damage/fibrosis in Mdr2-/- mice and human cholangiocarcinoma tumorigenesis. Hepatology (Baltimore, Md.) 59 29601088
2018 Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset. Hepatology communications 59 29761167
2012 Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations. Virchows Archiv : an international journal of pathology 58 22331132
2018 Colesevelam attenuates cholestatic liver and bile duct injury in Mdr2 mice by modulating composition, signalling and excretion of faecal bile acids. Gut 56 29636383
1992 High expression of the mdr3 multidrug-resistance gene in advanced-stage chronic lymphocytic leukemia. Blood 56 1347708
2014 Molecular mechanisms for biliary phospholipid and drug efflux mediated by ABCB4 and bile salts. BioMed research international 55 25133187
2013 Expression of MDR1 and MDR3 gene products in paclitaxel-, doxorubicin- and vincristine-resistant cell lines. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 53 24140176
1998 Biliary secretion of alpha-tocopherol and the role of the mdr2 P-glycoprotein in rats and mice. Archives of biochemistry and biophysics 53 9473291
2009 ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy. Journal of medical genetics 52 19584064
1999 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) induce hepatic expression of the phospholipid translocase mdr2 in rats. Gastroenterology 51 10464145
2019 ABCB4 disease: Many faces of one gene deficiency. Annals of hepatology 48 31759867
2009 Liver diseases related to MDR3 (ABCB4) gene deficiency. Frontiers in bioscience (Landmark edition) 48 19273348
2014 Phosphorylation of ABCB4 impacts its function: insights from disease-causing mutations. Hepatology (Baltimore, Md.) 43 24723470
2018 Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/- mice by diminishing senescence of cholangiocytes. Laboratory investigation; a journal of technical methods and pathology 42 29977037
2011 Two promoter rearrangements in a drug efflux transporter gene are responsible for the appearance and spread of multidrug resistance phenotype MDR2 in Botrytis cinerea isolates in French and German vineyards. Phytopathology 42 21679037
2011 First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis. European journal of human genetics : EJHG 42 21989363
2018 Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2 mice. Journal of lipid research 41 30416103
2015 ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression. Journal of gastroenterology 41 26324191
2018 Ursodeoxycholate inhibits mast cell activation and reverses biliary injury and fibrosis in Mdr2-/- mice and human primary sclerosing cholangitis. Laboratory investigation; a journal of technical methods and pathology 39 30143751
2016 BSEP and MDR3: Useful Immunohistochemical Markers to Discriminate Hepatocellular Carcinomas From Intrahepatic Cholangiocarcinomas and Hepatoid Carcinomas. The American journal of surgical pathology 36 26735860
2017 Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chemical research in toxicology 35 28437613
2020 Review article: liver disease in adults with variants in the cholestasis-related genes ABCB11, ABCB4 and ATP8B1. Alimentary pharmacology & therapeutics 34 33070363
2021 Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2  mouse. JHEP reports : innovation in hepatology 33 33870156
2019 Downregulation of hepatic stem cell factor by Vivo-Morpholino treatment inhibits mast cell migration and decreases biliary damage/senescence and liver fibrosis in Mdr2-/- mice. Biochimica et biophysica acta. Molecular basis of disease 31 31521820
2014 All-trans-retinoic acid improves cholestasis in α-naphthylisothiocyanate-treated rats and Mdr2-/- mice. The Journal of pharmacology and experimental therapeutics 31 24492652
2023 Human Placental Mesenchymal Stem Cells Relieve Primary Sclerosing Cholangitis via Upregulation of TGR5 in Mdr2-/- Mice and Human Intrahepatic Cholangiocyte Organoid Models. Research (Washington, D.C.) 30 37600495
2016 Functional Rescue of Trafficking-Impaired ABCB4 Mutants by Chemical Chaperones. PloS one 30 26900700
1997 Overexpression of mdr2 gene by peroxisome proliferators in the mouse liver. Journal of hepatology 30 9210621
2020 Carriers of ABCB4 gene variants show a mild clinical course, but impaired quality of life and limited risk for cholangiocarcinoma. Liver international : official journal of the International Association for the Study of the Liver 29 32893960
2013 Detergent screening and purification of the human liver ABC transporters BSEP (ABCB11) and MDR3 (ABCB4) expressed in the yeast Pichia pastoris. PloS one 28 23593265
2010 ABCB4 deficiency: A family saga of early onset cholelithiasis, sclerosing cholangitis and cirrhosis and a novel mutation in the ABCB4 gene. Hepatology research : the official journal of the Japan Society of Hepatology 28 20887599
2015 Heterozygous ABCB4 mutations in children with cholestatic liver disease. Liver international : official journal of the International Association for the Study of the Liver 27 26153658
1995 Regulation of protein secretion into bile: studies in mice with a disrupted mdr2 p-glycoprotein gene. Gastroenterology 27 7498666
2014 Variations of ABCB4 and ABCB11 genes are associated with primary intrahepatic stones. Molecular medicine reports 25 25323205
2024 Glioblastoma stem cells deliver ABCB4 transcribed by ATF3 via exosomes conferring glioblastoma resistance to temozolomide. Cell death & disease 24 38710703
2022 Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis. Genes 24 35741809
2014 ABCB4: Insights from pathobiology into therapy. Clinics and research in hepatology and gastroenterology 24 24953525
2013 Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction. European journal of human genetics : EJHG 24 24045840
1999 Decreased Na+-dependent taurocholate uptake and low expression of the sinusoidal Na+-taurocholate cotransporting protein (Ntcp) in livers of mdr2 P-glycoprotein-deficient mice. Journal of hepatology 23 9927146
2017 8-Methoxypsoralen disrupts MDR3-mediated phospholipids efflux and bile acid homeostasis and its relevance to hepatotoxicity. Toxicology 22 28552422
2014 Zebrafish Abcb4 is a potential efflux transporter of microcystin-LR. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 22 25193616
2007 Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice. Molecular cancer therapeutics 22 17431106
2014 ABCB4 is frequently epigenetically silenced in human cancers and inhibits tumor growth. Scientific reports 21 25367630
2013 Hepatobiliary anomalies associated with ABCB4/MDR3 deficiency in adults: a pictorial essay. Insights into imaging 21 23591976
2012 The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 22982378
1995 Characterization of the promoter region of the human MDR3 P-glycoprotein gene. Biochimica et biophysica acta 21 7893760
2023 Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis. JHEP reports : innovation in hepatology 20 37841639
2023 GLP-2 Improves Hepatic Inflammation and Fibrosis in Mdr2-/- Mice Via Activation of NR4a1/Nur77 in Hepatic Stellate Cells and Intestinal FXR Signaling. Cellular and molecular gastroenterology and hepatology 19 37572734
2008 Role of hepatic phospholipids in development of liver injury in Mdr2 (Abcb4) knockout mice. Liver international : official journal of the International Association for the Study of the Liver 19 18410282
2021 ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes. The Journal of pediatrics 18 33915153
2018 Thyroid hormone receptor β1 stimulates ABCB4 to increase biliary phosphatidylcholine excretion in mice. Journal of lipid research 18 29895698
2014 Altered expression and function of canalicular transporters during early development of cholestatic liver injury in Abcb4-deficient mice. American journal of physiology. Gastrointestinal and liver physiology 18 24481602
2007 The Multiple Facets of ABCB4 (MDR3) Deficiency. Current treatment options in gastroenterology 18 18221610
2024 Trichophyton indotineae Erg1Ala448Thr Strain Expressed Constitutively High Levels of Sterol 14-α Demethylase Erg11B mRNA, While Transporter MDR3 and Erg11A mRNA Expression Was Induced After Addition of Short Chain Azoles. Journal of fungi (Basel, Switzerland) 17 39590650

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