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http://purl.uniprot.org/citations/19027009http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/19027009http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/19027009http://www.w3.org/2000/01/rdf-schema#comment"

Background & aims

Progressive familial intrahepatic cholestasis 1 (PFIC1) results from mutations in ATP8B1, a putative aminophospholipid flippase. Conflicting hypotheses have been proposed for the pathogenesis of PFIC1. The aim of this study was to determine whether ATP8B1 deficiency produces cholestasis by altering the activity of the farnesoid X receptor (FXR) or by impairing the structure of the canalicular membrane.

Methods

ATP8B1/Atp8b1 was knocked down in human and rat hepatocytes and Caco2 cells using adenoviral and oligonucleotide small interfering RNAs.

Results

ATP8B1 messenger RNA and protein expression was greatly reduced in human and rat cells. In contrast, FXR expression and several FXR-dependent membrane transporters (bile salt export pump [BSEP], multidrug resistance-associated protein [MRP] 2) were unchanged at messenger RNA or protein levels in ATP8B1-deficient cells, whereas Mrp3 and Mrp4 were up-regulated in rat hepatocytes. FXR activity remained intact in these cells, as evidenced by 6alpha-ethyl chenodeoxycholic acid-mediated induction of small heterodimer partner, BSEP, and multidrug-resistant protein (MDR) 3/Mdr2. Fluorescent substrate excretion assays indicate that Bsep function was significantly reduced in Atp8b1-deficient rat hepatocytes, although Bsep remained localized to the canalicular membrane. Exposure to the hydrophobic bile acid CDCA resulted in focal areas of canalicular membrane disruption by electron microscopy and luminal accumulation of NBD-phosphatidylserine, consistent with the function of Atp8b1 as an aminophospholipid flippase.

Conclusions

ATP8B1 deficiency predisposes to cholestasis by favoring bile acid-induced injury in the canalicular membrane but does not directly affect FXR expression, which may occur in PFIC1 as a secondary phenomenon associated with cholestasis."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.org/dc/terms/identifier"doi:10.1053/j.gastro.2008.10.025"xsd:string
http://purl.uniprot.org/citations/19027009http://purl.org/dc/terms/identifier"doi:10.1053/j.gastro.2008.10.025"xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Nguyen T."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Nguyen T."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Boyer J.L."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Boyer J.L."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Cai S.Y."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Cai S.Y."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Gautam S."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Gautam S."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Rahner C."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Rahner C."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Soroka C.J."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/author"Soroka C.J."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/date"2009"xsd:gYear
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/date"2009"xsd:gYear
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/name"Gastroenterology"xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/name"Gastroenterology"xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/pages"1060-1069"xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/pages"1060-1069"xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/title"ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained."xsd:string
http://purl.uniprot.org/citations/19027009http://purl.uniprot.org/core/title"ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained."xsd:string
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