Affinage

ATP8B1

Phospholipid-transporting ATPase IC · UniProt O43520

Length
1251 aa
Mass
143.7 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: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP8B1 (FIC1) is a P4-ATPase phospholipid flippase that maintains plasma membrane lipid asymmetry at apical/canalicular surfaces and thereby protects epithelial membranes and organizes apical polarity (PMID:17948906, PMID:16799980). It functions as an obligate heterodimer, requiring the accessory protein CDC50A (or CDC50B) for exit from the endoplasmic reticulum and trafficking to the apical membrane of hepatocytes, cholangiocytes, enterocytes, and other epithelia (PMID:17948906, PMID:15496606); once at the canalicular membrane it actively flips phosphatidylserine from the outer to the inner leaflet (PMID:17948906, PMID:11682026). Cryo-EM structures define a catalytic cycle of autophosphorylation gated by autoinhibitory N- and C-terminal tails, with full activation requiring tail release and binding of phosphoinositides—most markedly PI(3,4,5)P3—and lipid substrate, while Ser403 recognizes the sn-2 ester bond of glycerophospholipid substrates of broad specificity including phosphatidylinositol (PMID:35416773, PMID:37980352, PMID:35349344). In the liver this flippase activity preserves canalicular membrane integrity against hydrophobic bile salts, acting complementarily with the ABCB4 floppase: loss of ATP8B1 permits bile salt extraction of phosphatidylserine, cholesterol, and ectoenzymes, a defect rescued genetically by removing ABCB4 (PMID:16799980, PMID:21820390, PMID:18466903). In epithelial cells ATP8B1 builds the apical domain by providing negatively charged lipids that cluster Cdc42 to enforce apical singularity (PMID:26416959), enables apical localization and function of the bile salt transporter SLC10A2/ASBT and of CFTR (PMID:25239307, PMID:27301931), mediates intestinal lysophosphatidylcholine absorption controlling hepatic choline supply (PMID:37990006), and supports tight junction barrier integrity via Claudin-4 (PMID:38366839). In lung epithelium ATP8B1 additionally acts as a cardiolipin importer, clearing cardiolipin from extracellular fluid through a basic residue-enriched motif to protect surfactant during pneumonia (PMID:20852622). Disease-causing mutations stratify by their effect on CDC50A binding and trafficking: severe PFIC1 mutations abolish the interaction and canalicular localization, whereas milder BRIC1 mutations retain partial function (PMID:19731236, PMID:25421123).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 High

    Establishing where FIC1/ATP8B1 acts: localizing the protein to the canalicular and apical epithelial membranes defined the cellular site at which its function must be exerted.

    Evidence Immunoblot of isolated rat canalicular membrane fractions and immunohistochemistry in rodent and human liver, with absence in PFIC1 patient canaliculi

    PMID:11682026

    Open questions at the time
    • Did not define molecular activity
    • Did not identify trafficking requirements
  2. 2004 High

    Distinguishing flippase function from direct bile acid transport: showing FIC1 does not transport taurocholate or alter BSEP/ASBT function, and that G308V mice maintain canalicular secretion, reframed ATP8B1 as a homeostatic membrane protector rather than a bile salt pump.

    Evidence Transport assays in polarized MDCK cells; G308V/G308V knock-in mouse with bile salt feeding/infusion challenges; multi-tissue immunohistochemistry

    PMID:14976163 PMID:15209631 PMID:15496606

    Open questions at the time
    • Mechanism connecting membrane state to bile salt homeostasis unresolved
    • Direct lipid substrate not yet demonstrated
  3. 2006 High

    Defining the in vivo consequence: Atp8b1-deficient mice lose canalicular phospholipid asymmetry and resistance to bile salts, establishing maintenance of membrane lipid asymmetry as the physiological role.

    Evidence Atp8b1-deficient mouse with perfused-liver bile salt infusion, biliary lipid/ectoenzyme analysis, and PFIC1 patient liver immunostaining

    PMID:16799980

    Open questions at the time
    • Did not establish biochemical flippase activity directly
    • Trafficking partners unknown
  4. 2008 High

    Identifying the obligate partner and direct activity: CDC50A/B are required for ER exit and surface delivery, and the complex directly translocates phosphatidylserine — the defining flippase activity.

    Evidence Heterologous co-expression in CHO and WIF-B9 cells with fluorescent PS translocation assays and immunofluorescence colocalization

    PMID:17948906

    Open questions at the time
    • Full substrate spectrum not defined
    • Structural basis of transport unknown
  5. 2008 High

    Resolving the mechanism of biliary cholesterol loss: in Atp8b1 deficiency cholesterol is extracted nonspecifically by bile salts independent of Abcg5/8, cementing the membrane-protection model.

    Evidence Atp8b1/Abcg8 double-knockout mice with LXR agonist and taurocholate challenge and biliary lipid analysis

    PMID:18466903

    Open questions at the time
    • Did not address extrahepatic roles
  6. 2009 High

    Linking genotype to phenotype mechanistically: PFIC1 mutations abolish CDC50A binding and trafficking while BRIC1 mutations retain residual function, explaining differential disease severity.

    Evidence Mutagenesis, reciprocal co-IP, and immunofluorescence localization across CHO and WIF-B9 cells

    PMID:19731236

    Open questions at the time
    • Did not quantify residual flippase activity per mutant
  7. 2009 High

    Testing an alternative FXR-regulation hypothesis: knockdown in primary hepatocytes left FXR intact but reduced Bsep function and caused CDCA-induced membrane disruption, favoring the flippase mechanism over transcriptional FXR control.

    Evidence siRNA knockdown in primary hepatocytes and Caco2 cells with FXR reporters, fluorescent substrate excretion, and canalicular EM; contrasted with HepG2 knockdown and FXR reporter/co-precipitation studies

    PMID:15317749 PMID:19027009 PMID:19228886 PMID:19381753

    Open questions at the time
    • Discrepant FXR-downregulation results in hepatoma cells unreconciled
    • Causal direction of FXR changes unclear in cell-context-dependent studies
  8. 2010 High

    Uncovering an extrahepatic activity: ATP8B1 imports cardiolipin from extracellular fluid via a basic-residue motif in lung epithelium, protecting surfactant during infection.

    Evidence In vitro cardiolipin binding/internalization assays, motif mapping, Atp8b1 mutant mouse with intratracheal cardiolipin and gene-transfer rescue, human validation

    PMID:20852622

    Open questions at the time
    • Relationship between cardiolipin import and canonical flippase cycle unresolved
  9. 2011 High

    Establishing complementarity with ABCB4: the ATP8B1-CDC50A flippase counteracts ABCB4-floppase toxicity, and removing ABCB4 prevents bile salt extraction in Atp8b1-null mice — a balanced bidirectional lipid system.

    Evidence HEK293T viability assay and Atp8b1/Abcb4 double-knockout mice with bile salt feeding and biliary analysis

    PMID:21820390

    Open questions at the time
    • Quantitative stoichiometry of the two transporters not defined
  10. 2016 High

    Extending function to epithelial polarity and channel delivery: ATP8B1 clusters Cdc42 to enforce apical singularity and is required for apical localization of CFTR and SLC10A2.

    Evidence shRNA/siRNA depletion in intestinal and pulmonary epithelial cells with FRAP, surface biotinylation, transport/short-circuit current assays, and rescue experiments

    PMID:25239307 PMID:26416959 PMID:27301931

    Open questions at the time
    • Whether channel mislocalization is a direct or indirect consequence of altered lipid asymmetry not fully separated
  11. 2023 High

    Defining the structural catalytic mechanism: cryo-EM resolved autoinhibition by N/C-terminal tails, release by substrate and bile acids, PI(3,4,5)P3 activation, broad lipid specificity, and Ser403 sn-2 ester recognition.

    Evidence Multiple high-resolution cryo-EM structures with ATPase assays, truncation mutagenesis, peptide rescue, PI(3,4,5)P3 activation, and S403 mutagenesis

    PMID:35349344 PMID:35416773 PMID:37980352

    Open questions at the time
    • Physiological trigger ordering of PI(3,4,5)P3 versus bile acid release in vivo unresolved
  12. 2024 High

    Expanding the metabolic and barrier roles: intestinal ATP8B1 absorbs LPC to supply hepatic choline (preventing steatohepatitis) and supports tight junction barrier integrity via Claudin-4.

    Evidence IEC-specific Atp8b1 knockout mice with metabolomics and choline rescue; Caco-2 barrier assays and DSS colitis with co-IP and patient biopsy validation; pancreatic acinar Atp8b1 epigenetic regulation studies

    PMID:36273194 PMID:37990006 PMID:38366839

    Open questions at the time
    • Molecular identity of barrier-relevant ATP8B1 partners only partially defined
    • Whether LPC handling reflects flippase or import activity unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single flippase coordinates lipid asymmetry with diverse downstream outputs — Cdc42 polarity, channel trafficking, barrier formation, and tissue-specific lipid import — within a unified biophysical mechanism remains unresolved.
  • No integrated model linking flippase cycle to apical protein recruitment
  • Tissue-specific regulation of ATP8B1 expression/activity incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0005215 transporter activity 2 GO:0016787 hydrolase activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-9609507 Protein localization 3 R-HSA-1643685 Disease 2 R-HSA-382551 Transport of small molecules 2
Partners
ABCB4CDC42CDC50ACDC50BCFTRCLDN4SLC10A2
Complex memberships
ATP8B1-CDC50A flippase heterodimer

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 ATP8B1 requires CDC50A (and CDC50B) as accessory proteins for exit from the endoplasmic reticulum and trafficking to the plasma membrane; when co-expressed with CDC50 proteins, ATP8B1 functions as a phosphatidylserine flippase at the plasma membrane, reducing phosphatidylserine exposure on the outer leaflet by 17–25%. Heterologous expression in CHO cells and WIF-B9 hepatocyte-like cells; co-expression of ATP8B1 with CDC50A/CDC50B; fluorescently labeled phosphatidylserine translocation assays; immunofluorescence colocalization Hepatology High 17948906
2006 Atp8b1 deficiency in mice causes loss of phospholipid asymmetry at the canalicular membrane (increased biliary excretion of phosphatidylserine, cholesterol, and ectoenzymes), rendering the canalicular membrane less resistant to hydrophobic bile salts and subsequently impairing bile salt transport into bile. Atp8b1-deficient mouse model; perfused liver bile salt infusion; biliary lipid and ectoenzyme analysis; liver histology; immunostaining of liver specimens from PFIC1 patients Hepatology High 16799980
2001 FIC1/ATP8B1 protein localizes to the canalicular membrane of hepatocytes and to the apical membrane of cholangiocytes, as demonstrated by immunoblot of isolated membrane fractions and immunohistochemistry; it is absent from canalicular membranes in PFIC1 patients. Immunoblot analysis of isolated rat liver membrane vesicles (canalicular fraction enrichment); immunohistochemistry and double-label immunofluorescence in liver sections; analysis of PFIC1 patient liver Journal of Hepatology High 11682026
2011 ATP8B1-CDC50A complex (phosphatidylserine flippase) acts complementarily with ABCB4 (phosphatidylcholine floppase) to maintain canalicular membrane integrity; overexpression of ABCB4 is toxic to cells, and this toxicity is counteracted by co-expression of the ATP8B1-CDC50A complex; in Atp8b1-deficient mice, bile salt feeding induces extraction of phosphatidylserine and ectoenzymes from the canalicular membrane, which is prevented in Atp8b1/Abcb4 double-knockout mice. Overexpression in HEK293T cells with viability assay; Atp8b1/Abcb4 double-knockout mouse model; bile salt feeding challenge; biliary lipid and ectoenzyme analysis Gastroenterology High 21820390
2022 Cryo-EM structure of human ATP8B1-CDC50A at 3.1 Å reveals that ATP8B1 is autoinhibited by its N- and C-terminal tails, which interact with the catalytic sites and flexible domain interfaces; ATP hydrolysis is activated by truncation of the C-terminus and requires phosphoinositides (most markedly PI(3,4,5)P3); removal of both N- and C-termini results in full activation; a synthetic peptide mimicking the C-terminal segment can restore inhibition. Cryo-EM structure determination (3.1 Å); in vitro ATPase activity assays with truncation mutants; PI(3,4,5)P3 activation assay; synthetic peptide inhibition assay eLife High 35416773
2023 Nine cryo-EM structures of ATP8B1-CDC50A at 2.4–3.1 Å resolution reveal the catalytic cycle including autophosphorylation from ATP (with water occupying the transport site upon phosphorylation), two distinct autoinhibited states (closed and outward-open), a PI(3,4,5)P3 binding site in an electropositive pocket between TM segments 5, 7, 8, and 10, broad lipid specificity including phosphatidylinositol as a transport substrate, and a critical role of Ser403 in recognizing the sn-2 ester bond of glycerophospholipid substrates. Cryo-EM structure determination (2.4–3.1 Å, nine structures); in vitro functional studies; molecular dynamics/computational studies; site-directed mutagenesis of S403 Nature Communications High 37980352
2022 Cryo-EM structures of ATP8B1 complexed with CDC50A and CDC50B reveal an autoinhibited state that is released upon substrate binding; bile acids facilitate release of autoinhibition, suggesting a feedback loop where bile acids modulate lipid asymmetry maintenance by ATP8B1. Cryo-EM structure determination; functional assays; substrate binding experiments Proceedings of the National Academy of Sciences of the United States of America High 35349344
2009 PFIC1 missense mutations (G308V, D554N, G1040R) abolish or severely reduce ATP8B1 interaction with CDC50A and prevent canalicular membrane localization entirely, while BRIC1/ICP missense mutations (D70N, I661T, R867C) show reduced but not absent CDC50A interaction and retain residual canalicular localization; this provides a molecular explanation for the difference in disease severity between PFIC1 and BRIC1. Mutagenesis and co-expression in CHO cells; co-immunoprecipitation; subcellular localization by immunofluorescence in WIF-B9 cells; protein stability assessment Hepatology High 19731236
2010 Atp8b1 functions as a cardiolipin importer in lung epithelial cells; it binds and internalizes cardiolipin from extracellular fluid via a basic residue-enriched motif; Atp8b1 mutant mice and humans with ATP8B1 mutations show elevated cardiolipin in lung fluid during pneumonia, impairing surfactant function. Peptide encompassing the cardiolipin-binding motif or Atp8b1 gene transfer reduces lung injury in mice. In vitro cardiolipin binding and internalization assays; Atp8b1 mutant mouse model; intratracheal cardiolipin administration; gene transfer in mice; identification of basic residue-enriched binding motif Nature Medicine High 20852622
2004 FIC1/ATP8B1 does not transport taurocholate and its overexpression has no effect on the function of BSEP or ASBT (apical bile acid transporters) in polarized MDCK cells. Apical secretion and apical uptake assays in polarized MDCK cells transfected with FIC1, BSEP, and/or ASBT; [3H]taurocholate transport measurement Journal of Gastroenterology and Hepatology Medium 15209631
2004 Mutations in ATP8B1 result in reduced hepatic expression of FXR (farnesoid X receptor) and its target genes (BSEP, small heterodimer partner), based on gene expression analysis of liver from a PFIC1 patient; this implicates FIC1 in FXR-dependent bile acid homeostasis. Gene expression analysis (mRNA levels) in liver specimens; comparison of PFIC1 patient vs controls and other cholestatic disease patients Human Molecular Genetics Low 15317749
2008 ATP8B1 knockdown in human and rat hepatocytes does not alter FXR expression or activity (FXR-dependent transporter induction is intact), but Bsep function is significantly reduced and exposure of the canalicular membrane to the hydrophobic bile acid CDCA causes focal membrane disruption and luminal accumulation of NBD-phosphatidylserine, consistent with Atp8b1 acting as an aminophospholipid flippase that protects canalicular membrane integrity. siRNA-mediated knockdown of ATP8B1/Atp8b1 in human and rat hepatocytes and Caco2 cells; FXR reporter assays; fluorescent substrate excretion assays; electron microscopy of canalicular membrane; immunofluorescence Gastroenterology High 19027009
2009 ATP8B1 knockdown in HepG2 cells specifically downregulates FXR mRNA and protein, as well as FXR target genes (ABCB11/BSEP, SHP, UGT); treatment with FXR agonist GW4064 can partially rescue FXR downregulation; other nuclear receptors (PXR, CAR) and transcription factors (HNF-1α, HNF-4α) are unaffected. siRNA-mediated ATP8B1 knockdown in HepG2 cells; quantitative RT-PCR and Western blot for FXR and target genes; FXR agonist treatment American Journal of Physiology - Gastrointestinal and Liver Physiology Medium 19228886
2009 Wild-type FIC1 expression increases FXR-dependent transcription in luciferase assays; three PFIC1 mutants (G308V, T456M, D554N) show reduced stimulatory effect on FXR activity and fail to interact with CDC50A in co-precipitation assays; CDC50A co-expression enhances FIC1-mediated FXR stimulation only with wild-type FIC1. Luciferase reporter assays for FXR-dependent transcription; co-precipitation assays for FIC1-CDC50A interaction; localization studies Journal of Gastroenterology Medium 19381753
2004 Fic1 protein is localized to apical membranes of enterocytes, pancreatic acinar cells, gastric pit epithelial cells, and hepatocytes/cholangiocytes; in the small intestine, Fic1 expression is developmentally regulated and increases postnatally in mice. Immunoblot; RT-PCR; immunohistochemistry of mouse and human gastrointestinal tissues at multiple postnatal time points Pediatric Research Medium 15496606
2014 The ATP8B1-CDC50A heterodimer is essential for the apical membrane localization and activity of SLC10A2/ASBT (apical sodium-dependent bile salt transporter) in intestinal Caco-2 cells; depletion of ATP8B1 causes impaired apical membrane insertion of SLC10A2, reducing bile salt uptake. siRNA-mediated ATP8B1 depletion in Caco-2 cells; bile salt transport assay; apical membrane biotinylation; co-immunoprecipitation of endogenous ATP8B1 with CDC50A; fecal bile salt analysis in PFIC1 patients Biochimica et Biophysica Acta High 25239307
2015 ATP8B1 enables Cdc42 clustering at the apical membrane during enterocyte polarization by providing negatively charged membrane lipids that interact with the polybasic region of Cdc42; loss of ATP8B1 increases Cdc42 mobility and results in formation of multiple apical domains (loss of singularity); re-establishing Cdc42 clustering by membrane tethering or reducing its diffusion restores normal apical membrane size. shRNA-mediated ATP8B1 depletion in intestinal cells; FRAP and live imaging of Cdc42 mobility; overexpression of Cdc42 mutant defective in lipid binding; rescue experiments with membrane-tethered Cdc42 Journal of Cell Biology High 26416959
2016 ATP8B1 is essential for correct apical localization of CFTR (cystic fibrosis transmembrane conductance regulator) in human intestinal and pulmonary epithelial cells; ATP8B1 depletion reduces CFTR protein at the apical membrane and impairs CFTR-mediated chloride transport; apical membrane insertion of ectopically expressed CFTR is strongly impaired in ATP8B1-depleted cells. siRNA/shRNA depletion of ATP8B1 in T84 intestinal and pulmonary epithelial cells; short-circuit current measurement; genetically encoded fluorescent chloride sensor; apical CFTR surface expression analysis Biochimica et Biophysica Acta High 27301931
2016 Several CFTR corrector compounds (4-PBA, SAHA, NB-DNJ, C4, C5, C13, C17) improve plasma membrane targeting of the misfolded p.I661T-ATP8B1 mutant in vitro; combination of SAHA and C4 additively improves cell surface abundance of p.I661T-ATP8B1. Cell surface biotinylation; immunofluorescence in CHO and polarized WIF-B9 cells; ATPase activity assay of analogous mutant p.L622T-ATP8A2 Journal of Hepatology Medium 26879107
2008 Atp8b1 deficiency leads to increased biliary cholesterol excretion that is independent of Abcg5/Abcg8 transporter activity; instead, it results from reduced detergent resistance and nonspecific extraction of cholesterol from the canalicular membrane by bile salts. Atp8b1/Abcg8 double-knockout mouse model; LXR agonist feeding; taurocholate infusion; biliary cholesterol, bile salt, phospholipid, and ectoenzyme analysis Gastroenterology High 18466903
2023 Intestinal ATP8B1 regulates hepatic choline levels through apical membrane absorption of lysophosphatidylcholine (LPC) in enterocytes; IEC-specific Atp8b1 knockout mice develop steatohepatitis by 4 weeks due to LPC malabsorption and consequent hepatic choline deficiency; choline supplementation fully rescues the steatohepatitis phenotype. Intestinal epithelial cell-specific Atp8b1-knockout mice; metabolomic analysis; cell-based LPC uptake assays; choline supplementation rescue experiment; analysis of pediatric ATP8B1 deficiency patient samples Nature Communications High 37990006
2022 In chronic pancreatitis, Atp8b1 expression in pancreatic acinar cells is transcriptionally suppressed by H3K27me3-mediated promoter methylation; Atp8b1 promotes LPC production and macrophage efferocytosis; Bhlha15 is identified as a transcription factor that binds the Atp8b1 promoter and promotes its transcription; Atp8b1 complementation increases LPC and improves chronic pancreatitis outcomes. ATAC-seq; RNA-seq; H3K27me3 ChIP-seq; ChIP-qPCR; luciferase assays; AAV-mediated Atp8b1 overexpression in PRSS1 transgenic mice; flow cytometry; lipid metabolomics; ELISA Cell Death & Disease High 36273194
2024 ATP8B1 is important for establishment of the intestinal epithelial barrier; ATP8B1 knockdown in Caco-2 cells delays barrier formation and alters levels and localization of the tight junction protein Claudin-4 (CLDN4); ATP8B1-deficient mice are highly susceptible to DSS-induced colitis with increased intestinal permeability; co-immunoprecipitation in Caco2-BBE cells overexpressing ATP8B1-eGFP identifies binding partners. siRNA knockdown in Caco-2-BBE cells; epithelial barrier permeability assays; DSS-induced colitis in Atp8b1-deficient mice; co-immunoprecipitation; immunohistochemistry of UC and PFIC1 patient biopsies Journal of Crohn's & Colitis High 38366839
2004 Atp8b1(G308V/G308V) mutant mice show perturbed bile salt homeostasis (elevated serum bile salts, expansion of systemic bile salt pool upon feeding) but no impairment of canalicular bile secretion; failure of homeostasis occurs without defect in hepatic bile secretion; hydrophobic bile salt infusion causes cholestasis in wild-type but not mutant mice, which maintain high biliary output and more extensively rehydroxylate the bile salt. Knock-in mouse model (G308V/G308V); bile salt feeding and infusion challenges; serum and biliary bile salt analysis; liver histology Human Molecular Genetics High 14976163
2015 Eleven out of 14 ATP8B1 mutations at exon-intron boundaries result in complete exon skipping (aberrant splicing with absence of correctly spliced product), mostly associated with PFIC phenotype; three mutations lead to partially correct splicing and are associated with BRIC phenotype; amount of correctly spliced product inversely correlates with disease severity; modified U1 snRNAs complementary to mutated splice donor sites can rescue splicing defects. In vitro minigene splicing assay; modified U1 snRNA rescue experiments; correlation with clinical phenotype data Hepatology Medium 25421123

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology (Baltimore, Md.) 208 20232290
2004 Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology (Baltimore, Md.) 197 15239083
1997 Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity. Hepatology (Baltimore, Md.) 194 9214465
2008 ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity. Hepatology (Baltimore, Md.) 191 17948906
1993 Pattern formation in the limbs of Drosophila: bric à brac is expressed in both a gradient and a wave-like pattern and is required for specification and proper segmentation of the tarsus. Development (Cambridge, England) 183 7910551
2006 Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology (Baltimore, Md.) 170 16799980
2010 Differences in presentation and progression between severe FIC1 and BSEP deficiencies. Journal of hepatology 142 20447715
1995 Mechanisms of cell rearrangement and cell recruitment in Drosophila ovary morphogenesis and the requirement of bric à brac. Development (Cambridge, England) 125 7867498
2010 Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia. Nature medicine 120 20852622
2005 ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. Gut 115 15888793
2017 An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Scientific reports 107 28924228
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
2002 The bric à brac locus consists of two paralogous genes encoding BTB/POZ domain proteins and acts as a homeotic and morphogenetic regulator of imaginal development in Drosophila. Development (Cambridge, England) 100 11973274
2011 Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology 99 21820390
2001 FIC1 disease: a spectrum of intrahepatic cholestatic disorders. Seminars in liver disease 92 11745041
2007 Large-scale, lineage-specific expansion of a bric-a-brac/tramtrack/broad complex ubiquitin-ligase gene family in rice. The Plant cell 88 17720868
2001 FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte. Journal of hepatology 87 11682026
2016 Broad-complex, tramtrack, and bric-à-brac (BTB) proteins: Critical regulators of development. Genesis (New York, N.Y. : 2000) 86 27521773
2004 Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. Human molecular genetics 86 15317749
2004 A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion. Human molecular genetics 83 14976163
2008 ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology 82 19027009
2003 Semi quantitative expression analysis of MDR3, FIC1, BSEP, OATP-A, OATP-C,OATP-D, OATP-E and NTCP gene transcripts in 1st and 3rd trimester human placenta. Placenta 80 12495658
1995 The BTB domain of bric à brac mediates dimerization in vitro. Molecular and cellular biology 76 7760839
1989 Nucleotide sequences of fic and fic-1 genes involved in cell filamentation induced by cyclic AMP in Escherichia coli. Journal of bacteriology 74 2546924
2005 Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy. European journal of human genetics : EJHG 73 15657619
2002 FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels. The Journal of pediatrics 72 11815775
2000 A missense mutation in FIC1 is associated with greenland familial cholestasis. Hepatology (Baltimore, Md.) 68 11093741
2009 Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular localization of ATP8B1. Hepatology (Baltimore, Md.) 61 19731236
2013 BRIC-seq: a genome-wide approach for determining RNA stability in mammalian cells. Methods (San Diego, Calif.) 58 23872059
2022 Maralixibat for the treatment of PFIC: Long-term, IBAT inhibition in an open-label, Phase 2 study. Hepatology communications 51 35507739
2004 Fic1 is expressed at apical membranes of different epithelial cells in the digestive tract and is induced in the small intestine during postnatal development of mice. Pediatric research 51 15496606
2017 Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing. Journal of gastroenterology 48 29238877
2013 Hepatotoxicity from anabolic androgenic steroids marketed as dietary supplements: contribution from ATP8B1/ABCB11 mutations? Liver international : official journal of the International Association for the Study of the Liver 48 23750872
2021 Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency. Hepatology (Baltimore, Md.) 44 33666275
2008 Abcg5/8 independent biliary cholesterol excretion in Atp8b1-deficient mice. Gastroenterology 44 18466903
2016 The Caenorhabditis elegans Protein FIC-1 Is an AMPylase That Covalently Modifies Heat-Shock 70 Family Proteins, Translation Elongation Factors and Histones. PLoS genetics 43 27138431
2001 Bile salt export pump is highly conserved during vertebrate evolution and its expression is inhibited by PFIC type II mutations. American journal of physiology. Gastrointestinal and liver physiology 38 11447010
2022 Autoinhibition and regulation by phosphoinositides of ATP8B1, a human lipid flippase associated with intrahepatic cholestatic disorders. eLife 37 35416773
2011 Recovery of graft steatosis and protein-losing enteropathy after biliary diversion in a PFIC 1 liver transplanted child. Pediatric transplantation 37 21672103
2002 Limb type-specific regulation of bric a brac contributes to morphological diversity. Development (Cambridge, England) 37 11830570
2018 Function of BriC peptide in the pneumococcal competence and virulence portfolio. PLoS pathogens 36 30308062
2020 Review article: liver disease in adults with variants in the cholestasis-related genes ABCB11, ABCB4 and ATP8B1. Alimentary pharmacology & therapeutics 34 33070363
2018 Cis-regulatory evolution integrated the Bric-à-brac transcription factors into a novel fruit fly gene regulatory network. eLife 34 29297463
2014 The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells. Biochimica et biophysica acta 34 25239307
2019 Prevention of Cholestatic Liver Disease and Reduced Tumorigenicity in a Murine Model of PFIC Type 3 Using Hybrid AAV-piggyBac Gene Therapy. Hepatology (Baltimore, Md.) 33 31099022
2016 Progressive Familial Intrahepatic Cholestasis (PFIC) in Indian Children: Clinical Spectrum and Outcome. Journal of clinical and experimental hepatology 33 27746616
1999 Growth and development, and auxin polar transport in higher plants under microgravity conditions in space: BRIC-AUX on STS-95 space experiment. Journal of plant research 33 11543177
2001 The BTB/POZ domain of the regulatory proteins Bric à brac 1 (BAB1) and Bric à brac 2 (BAB2) interacts with the novel Drosophila TAF(II) factor BIP2/dTAF(II)155. Developmental biology 30 11543621
2020 New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin. Journal of human genetics 29 32759993
2016 Identification of Fic-1 as an enzyme that inhibits bacterial DNA replication by AMPylating GyrB, promoting filament formation. Science signaling 29 26814232
2023 Activation and substrate specificity of the human P4-ATPase ATP8B1. Nature communications 28 37980352
2022 Structural insights into the activation of autoinhibited human lipid flippase ATP8B1 upon substrate binding. Proceedings of the National Academy of Sciences of the United States of America 28 35349344
2021 bric à brac controls sex pheromone choice by male European corn borer moths. Nature communications 28 33990556
1997 Progressive familial intrahepatic cholestasis (PFIC): evidence for genetic heterogeneity by exclusion of linkage to chromosome 18q21-q22. Human genetics 28 9272158
1997 Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64. Human genetics 28 9272159
1988 Cloning of the fic-1 gene involved in cell filamentation induced by cyclic AMP and construction of a delta fic Escherichia coli strain. Journal of bacteriology 28 2842288
2016 Rescue of defective ATP8B1 trafficking by CFTR correctors as a therapeutic strategy for familial intrahepatic cholestasis. Journal of hepatology 27 26879107
2007 Expression and clinical role of the bric-a-brac tramtrack broad complex/poxvirus and zinc protein NAC-1 in ovarian carcinoma effusions. Human pathology 27 17391728
2021 Light-Response Bric-A-Brack/Tramtrack/Broad proteins mediate cryptochrome 2 degradation in response to low ambient temperature. The Plant cell 26 34463721
2003 The Drosophila melanogaster BTB proteins bric à brac bind DNA through a composite DNA binding domain containing a pipsqueak and an AT-Hook motif. Nucleic acids research 26 12954775
1999 Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC. Human genetics 25 10323248
2009 Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064. American journal of physiology. Gastrointestinal and liver physiology 23 19228886
2018 bric à brac (bab), a central player in the gene regulatory network that mediates thermal plasticity of pigmentation in Drosophila melanogaster. PLoS genetics 22 30067846
2003 FIC1, a P-type ATPase linked to cholestatic liver disease, has homologues (ATP8B2 and ATP8B3) expressed throughout the body. Biochimica et biophysica acta 22 12880872
2015 Analysis of aberrant pre-messenger RNA splicing resulting from mutations in ATP8B1 and efficient in vitro rescue by adapted U1 small nuclear RNA. Hepatology (Baltimore, Md.) 20 25421123
2015 ATP8B1-mediated spatial organization of Cdc42 signaling maintains singularity during enterocyte polarization. The Journal of cell biology 20 26416959
2012 NR1H4 analysis in patients with progressive familial intrahepatic cholestasis, drug-induced cholestasis or intrahepatic cholestasis of pregnancy unrelated to ATP8B1, ABCB11 and ABCB4 mutations. Clinics and research in hepatology and gastroenterology 20 23142591
2008 Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion. BMC gastroenterology 20 18937870
2021 Competence-Associated Peptide BriC Alters Fatty Acid Biosynthesis in Streptococcus pneumoniae. mSphere 19 34192504
2014 A Comprehensive Review of Progressive Familial Intrahepatic Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters. Gastroenterology research 19 27785268
2007 Intestinal bile salt absorption in Atp8b1 deficient mice. Journal of hepatology 19 17448567
2021 ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes. The Journal of pediatrics 18 33915153
2019 Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice. Aging 18 30636723
2015 Two Case Reports of Successful Treatment of Cholestasis With Steroids in Patients With PFIC-2. Pediatrics 17 25847799
2009 FIC1-mediated stimulation of FXR activity is decreased with PFIC1 mutations in HepG2 cells. Journal of gastroenterology 17 19381753
2004 Taurocholate transport by hepatic and intestinal bile acid transporters is independent of FIC1 overexpression in Madin-Darby canine kidney cells. Journal of gastroenterology and hepatology 17 15209631
2010 Characterization of ATP8B1 gene mutations and a hot-linked mutation found in Chinese children with progressive intrahepatic cholestasis and low GGT. Journal of pediatric gastroenterology and nutrition 16 20038848
2003 The mouse nac1 gene, encoding a cocaine-regulated Bric-a-brac Tramtrac Broad complex/Pox virus and Zinc finger protein, is regulated by AP1. Neuroscience 15 14521994
2000 Abnormal hepatic sinusoidal bile acid transport in an Amish kindred is not linked to FIC1 and is improved by ursodiol. Gastroenterology 15 10889168
2013 Drosophila distal-less and Rotund bind a single enhancer ensuring reliable and robust bric-a-brac2 expression in distinct limb morphogenetic fields. PLoS genetics 14 23825964
2007 Depletion of high-density lipoprotein and appearance of triglyceride-rich low-density lipoprotein in a Japanese patient with FIC1 deficiency manifesting benign recurrent intrahepatic cholestasis. Journal of pediatric gastroenterology and nutrition 14 17592371
2022 ATP8B1 Knockdown Activated the Choline Metabolism Pathway and Induced High-Level Intracellular REDOX Homeostasis in Lung Squamous Cell Carcinoma. Cancers 13 35159102
2012 Characterization of urinary bile acids in a pediatric BRIC-1 patient: effect of rifampicin treatment. Clinica chimica acta; international journal of clinical chemistry 13 22525741
2022 Acinar ATP8b1/LPC pathway promotes macrophage efferocytosis and clearance of inflammation during chronic pancreatitis development. Cell death & disease 12 36273194
2020 Identification of ATP8B1 as a Tumor Suppressor Gene for Colorectal Cancer and Its Involvement in Phospholipid Homeostasis. BioMed research international 12 33062669
2017 Assessment of ATP8B1 Deficiency in Pediatric Patients With Cholestasis Using Peripheral Blood Monocyte-Derived Macrophages. EBioMedicine 12 29104077
2012 Nucleus Accumbens 1, a Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad protein binds to TAR DNA-binding protein 43 and has a potential role in Amyotrophic Lateral Sclerosis. Neuroscience 12 23022214
2021 Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations. Journal of clinical medicine 11 33924896
2016 The phospholipid flippase ATP8B1 mediates apical localization of the cystic fibrosis transmembrane regulator. Biochimica et biophysica acta 11 27301931
2016 High affinity anti-BSEP antibodies after liver transplantation for PFIC-2 - Successful treatment with immunoadsorption and B-cell depletion. Pediatric transplantation 11 27368585
2013 Mutational analysis of ATP8B1 in patients with chronic pancreatitis. PloS one 11 24260417
2024 The Phospholipid Flippase ATP8B1 is Involved in the Pathogenesis of Ulcerative Colitis via Establishment of Intestinal Barrier Function. Journal of Crohn's & colitis 10 38366839
2023 Structural insights into the recognition of telomeric variant repeat TTGGGG by broad-complex, tramtrack and bric-à-brac - zinc finger protein ZBTB10. The Journal of biological chemistry 10 36657642
2016 Global gene profiling of aging lungs in Atp8b1 mutant mice. Aging 10 27689529
2008 Successful treatment with colestimide for a bout of cholestasis in a Japanese patient with benign recurrent intrahepatic cholestasis caused by ATP8B1 mutation. Internal medicine (Tokyo, Japan) 10 18379143
2023 Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis. Nature communications 9 37990006
2022 A shared ancient enhancer element differentially regulates the bric-a-brac tandem gene duplicates in the developing Drosophila leg. PLoS genetics 9 35294439
2020 Nonsense variant of ATP8B1 gene in heterozygosis and benign recurrent intrahepatic cholestasis: A case report and review of literature. World journal of hepatology 9 32184942
2015 ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function. Digestive diseases (Basel, Switzerland) 9 26045263
2013 Polymorphisms in ABCB11 and ATP8B1 Associated with Development of Severe Intrahepatic Cholestasis in Hodgkin's Lymphoma. Journal of clinical and experimental hepatology 9 25755490

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