Familial intrahepatic cholestasis 1: Studies of localization and function

Ujházy, Peter; Ortiz, Daniel; Misra, Suniti; Li, Shohua; Moseley, James B.; Jones, Hazel C.; Arias, Irwin M.

doi:10.1053/jhep.2001.27663

Cited by 185 publications

(150 citation statements)

References 38 publications

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“…Two members of this subfamily including ATP8B1 have been reported to mediate aminophospholipid translocation in plasma membranes. 4,5 The physiological function of ATP8B1 protein and the mechanisms by which ATP8B1 deficiency leads to PFIC1 disease remain poorly understood. It was previously shown that ATP8B1 is expressed in different tissues such as the liver, the intestine, and the pancreas.…”

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

“…3,6 This tissue distribution is consistent with the fact that in PFIC1 cholestasis may be associated with extrahepatic manifestations such as pancreatic dysfunction or chronic diarrhea. 7,8 In rat and mouse species, ATP8B1 protein has been detected by immunochemical analyses in the two epithelial cell types of the liver (hepatocytes and cholangiocytes), and has been localized at the canalicular/apical domain of these cells, 5,9 while in the human liver, only an immunolocalization of ATP8B1 at the canalicular membrane of hepatocytes has been reported. 5,9 Evidence has been provided to indicate that ATP8B1 could interfere with transcriptional activity of the farnesoid X receptor (FXR).…”

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

“…7,8 In rat and mouse species, ATP8B1 protein has been detected by immunochemical analyses in the two epithelial cell types of the liver (hepatocytes and cholangiocytes), and has been localized at the canalicular/apical domain of these cells, 5,9 while in the human liver, only an immunolocalization of ATP8B1 at the canalicular membrane of hepatocytes has been reported. 5,9 Evidence has been provided to indicate that ATP8B1 could interfere with transcriptional activity of the farnesoid X receptor (FXR). FXR is a nuclear receptor for bile salts and a key transcriptional regulator of genes involved in the synthesis, conjugation and transport of bile salts, in the liver and in the intestine.…”

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

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Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

et al. 2006

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Recent reports in patients with PFIC1 have indicated that a gene defect in ATP8B1 could cause deregulations in bile salt transporters through decreased expression and/or activity of FXR. This study aimed to: (1) define ATP8B1 expression in human hepatobiliary cell types, and (2) determine whether ATP8B1 defect affects gene expressions related to bile secretion in these cells. ATP8B1 expression was detected by RT-PCR in hepatocytes and cholangiocytes isolated from normal human liver and gallbladder. ATP8B1 mRNA levels were 20-and 200-fold higher in bile duct and gallbladder epithelial cells, respectively, than in hepatocytes. RT-PCR analyses of the liver from two patients with PFIC1, one with PFIC2, one with biliary atresia, showed that, compared to normal liver, hepatic expressions of FXR, SHP, CYP7A1, ASBT were decreased at least by 90% in all cholestatic disorders. In contrast, NTCP transcripts were less decreased (by <30% vs. 97%) in PFIC1 as compared with other cholestatic disorders, while BSEP transcripts, in agreement with BSEP immunohistochemical signals, were normal or less decreased (by 50% vs. 97%). CFTR hepatic expression was decreased (by 80%), exclusively in PFIC1, while bile duct mass was not reduced, as ascertained by cytokeratin-19 immunolabeling. In Mz-ChA-2 human biliary epithelial cells, a significant decrease in CFTR expression was associated with ATP8B1 invalidation by siRNA. In conclusion, cholangiocytes are a major site of ATP8B1 hepatobiliary expression. A defect of ATP8B1 along with CFTR downregulation can impair the contribution of these cells to bile secretion, and potentially explain the extrahepatic cystic fibrosis-like manifestations that occur in PFIC1. (HEPATOLOGY 2006;43:1125-1134 P rogressive familial intrahepatic cholestasis (PFIC) represents a heterogeneous group of inherited disorders, in which cholestasis starts in infancy and generally leads to liver failure in childhood. Three types of PFIC, caused by mutations in three separate genes, are currently recognized. The first two types, PFIC1 and 2, share common phenotypic features, including normal or nearly normal serum ␥-glutamyl transpeptidase activity and little bile duct proliferation, that are unusual in other types of cholestatic liver diseases. 1 In PFIC2, mutations affect the ABCB11 gene, which encodes a bile salt transporter, the canalicular bile salt export pump (BSEP). 2 Thus, a defect in the extrusion of bile salts across the canalicular membrane of hepatocytes is the primary cause of cholestasis in PFIC2. In PFIC1, mutations affect the ATP8B1 gene, which encodes a protein also called FIC1. 3 ATP8B1 protein belongs to a subfamily of P-type adenosine triphosphatases. Two members of this subfamily including ATP8B1 have been reported to mediate aminophospholipid translocation in plasma membranes. 4,5 The physiological function of ATP8B1 protein and the mechanisms by which ATP8B1 deficiency leads to PFIC1 disease remain poorly understood. It was previously shown that ATP8B1 is expressed in different tissues such as th...

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Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

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Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

et al. 2006

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“…Flippase action can create an imbalance in phospholipid number between the two leaflets and cause bending of the membrane in the direction of lipid translocation (Graham, 2004). A large body of evidence indicates that P4-ATPases, which include the yeast Drs2, Dnf1, Dnf2, Dnf3, and Neo1 proteins, catalyze unidirectional phospholipid translocation from the extracellular leaflet of the plasma membrane, or the topologically equivalent lumenal leaflet of the Golgi and endosomes, to the cytosolic leaflet of these membranes (Tang et al, 1996;Gomes et al, 2000;Ujhazy et al, 2001;Pomorski et al, 2003;Natarajan et al, 2004;Saito et al, 2004;Alder-Baerens et al, 2006). Although a flippase activity has not been reconstituted with a purified P4-ATPase, we have shown that inactivation of a temperature-conditional mutant form of Drs2p (Drs2-ts) present in purified TGN membranes immediately disrupts phospholipid translocase activity measured with a fluorescent phospholipid derivative (Natarajan et al, 2004), supporting the view that Drs2p is a flippase.…”

Section: Introductionmentioning

confidence: 99%

P4-ATPase Requirement for AP-1/Clathrin Function in Protein Transport from the trans-Golgi Network and Early Endosomes

Liu

Surendhran

Nothwehr

et al. 2008

MBoC

107

155

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Drs2p is a resident type 4 P-type ATPase (P4-ATPase) and potential phospholipid translocase of the trans-Golgi network (TGN) where it has been implicated in clathrin function. However, precise protein transport pathways requiring Drs2p and how it contributes to clathrin-coated vesicle budding remain unclear. Here we show a functional codependence between Drs2p and the AP-1 clathrin adaptor in protein sorting at the TGN and early endosomes of Saccharomyces cerevisiae. Genetic criteria indicate that Drs2p and AP-1 operate in the same pathway and that AP-1 requires Drs2p for function. In addition, we show that loss of AP-1 markedly increases Drs2p trafficking to the plasma membrane, but does not perturb retrieval of Drs2p from the early endosome back to the TGN. Thus AP-1 is required at the TGN to sort Drs2p out of the exocytic pathway, presumably for delivery to the early endosome. Moreover, a conditional allele that inactivates Drs2p phospholipid translocase (flippase) activity disrupts its own transport in this AP-1 pathway. Drs2p physically interacts with AP-1; however, AP-1 and clathrin are both recruited normally to the TGN in drs2⌬ cells. These results imply that Drs2p acts independently of coat recruitment to facilitate AP-1/clathrin-coated vesicle budding from the TGN. INTRODUCTIONClathrin mediates protein transport between the plasma membrane, endosomes, and TGN through association with pathway-specific adaptors that link integral membrane cargo proteins to the clathrin lattice during vesicle formation. In mammalian cells, the ubiquitously expressed heterotetrameric AP-1A clathrin adaptor, composed of ␥, ␤1, 1A, and 1-adaptins, appears to mediate both anterograde transport of proteins from the TGN to early endosomes, as well as the retrograde trip back to the TGN (Hinners and Tooze, 2003;Robinson, 2004). For its role in anterograde transport of lysosomal enzymes, AP-1A collaborates with monomeric adaptors called GGAs (Golgi localized, ␥-earcontaining, Arf-binding proteins) to recruit the mannose-6-phosphate receptor into clathrin-coated vesicles (CCVs; Doray et al., 2002). The AP-1B complex, which differs from AP-1A by an alternate 1B subunit, has a functionally distinct role in sorting cargo from the TGN to the basolateral membrane of polarized epithelial cells (Folsch et al., 1999). In budding yeast, there is evidence that AP-1 mediates early endosome to TGN retrograde transport (Valdivia et al., 2002;Foote and Nothwehr, 2006), but no anterograde role for AP-1 has yet been described. The yeast GGAs appear to function independently of AP-1 to mediate delivery of cargo from the TGN to the late endosome (Black and Pelham, 2000). Deletion of genes encoding AP-1 subunits or GGAs has little consequence to growth of yeast. However, the combined deletion of AP-1 and GGA causes a severe growth defect, suggesting that these two adaptors mediate parallel transport pathways and that yeast cannot tolerate loss of both pathways (Costaguta et al., 2001;Hirst et al., 2001).The mechanism of AP-1/clathrin-coated vesicle ...

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“…In humans, a few biological disorders have been linked or attributed to genes from this subfamily. FIC1 (ATP8B) mutations cause familial intrahepatic cholestasis, a defect in bile secretion [5,6]. The ATP10C gene has been linked to Angelman syndrome and autism in some patients [7,8].…”

Section: Introductionmentioning

confidence: 99%

Mutational analysis of the Lem3p-Dnf1p putative phospholipid-translocating P-type ATPase reveals novel regulatory roles for Lem3p and a carboxyl-terminal region of Dnf1p independent of the phospholipid-translocating activity of Dnf1p in yeast

Noji

Yamamoto²,

Saito³

et al. 2006

Biochemical and Biophysical Research Communications

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Lem3p-Dnf1p is a putative aminophospholipid translocase (APLT) complex that is localized to the plasma membrane; Lem3p is required for Dnf1p localization to the plasma membrane. We have identified lem3 mutations, which did not affect formation or localization of the Lem3p-Dnf1p complex, but caused a synthetic growth defect with the null mutation of CDC50, a structurally and functionally redundant homologue of LEM3. Interestingly, these lem3 mutants exhibited nearly normal levels of NBDlabeled phospholipid internalization across the plasma membrane, suggesting that Lem3p may have other functions in addition to regulation of the putative APLT activity of Dnf1p at the plasma membrane. Similarly, deletion of the COOH-terminal cytoplasmic region of Dnf1p affected neither the localization nor the APLT activity of Dnf1p at the plasma membrane, but caused a growth defect in the cdc50∆ background.Our results suggest that the Lem3p-Dnf1p complex may play a role distinct from its plasma membrane APLT activity when it substitutes for the Cdc50p-Drs2p complex, its redundant partner in the endosomal/trans-Golgi network compartments.3

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Familial intrahepatic cholestasis 1: Studies of localization and function

Cited by 185 publications

References 38 publications

Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

P4-ATPase Requirement for AP-1/Clathrin Function in Protein Transport from the trans-Golgi Network and Early Endosomes

Mutational analysis of the Lem3p-Dnf1p putative phospholipid-translocating P-type ATPase reveals novel regulatory roles for Lem3p and a carboxyl-terminal region of Dnf1p independent of the phospholipid-translocating activity of Dnf1p in yeast

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