FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte

Eppens, Elaine F; Mil, Saskia W.C. van; Vree, Jana; Mok, King-Tong; Juijn, Jenneke A.; Elferink, Ronald P.J. Oude; Berger, Ruud; Houwen, Roderick H. J.; Klomp, Leo W. J.

doi:10.1016/s0168-8278(01)00158-1

Cited by 122 publications

(80 citation statements)

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“…1,13,14 Indeed, many PFIC1 patients exhibit extrahepatic symptoms, including pancreatitis, watery diarrhea, hearing loss, and elevated sweat salt concentrations, the latter like patients with deficiency in the cystic fibrosis transmembrane conductance regulator. 3,50 Our present results do not explain in any way the additional phenotypes observed in PFIC1 patients.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12] In the liver, ATP8B1 localizes to the apical membrane of epithe-lial cells, including hepatocytes and bile duct epithelial cells (cholangiocytes). [13][14][15] Ujhazy and colleagues have provided data to suggest that ATP8B1 is a flippase for phosphatidylserine (PS). 15 Bile formation is essential for disposition of lipophilic endobiotics and xenobiotics, for intestinal solubilization and absorption of dietary lipids and fat-soluble vitamins, and for the regulation of cholesterol homeostasis.…”

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confidence: 99%

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Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport

et al. 2006

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Progressive familial intrahepatic cholestasis type 1 (PFIC1, Byler disease, OMIM 211600) is a severe inherited liver disease caused by mutations in ATP8B1. ATP8B1 is a member of the type 4 subfamily of P-type ATPases, which are phospholipid flippases. PFIC1 patients generally develop end-stage liver disease before the second decade of life. The disease is characterized by impaired biliary bile salt excretion, but the mechanism whereby impaired ATP8B1 function results in cholestasis is unclear. In a mouse model for PFIC1, we observed decreased resistance of the hepatocanalicular membrane to hydrophobic bile salts as evidenced by enhanced biliary recovery of phosphatidylserine, cholesterol, and ectoenzymes. In liver specimens from PFIC1 patients, but not in those from control subjects, ectoenzyme expression at the canalicular membrane was markedly deficient. In isolated mouse livers Atp8b1 deficiency impaired the transport of hydrophobic bile salts into bile. In conclusion, our study shows that Atp8b1 deficiency causes loss of canalicular phospholipid membrane asymmetry that in turn renders the canalicular membrane less resistant toward hydrophobic bile salts. The loss of phospholipid asymmetry may subsequently impair bile salt transport and cause cholestasis. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/ index.html). (HEPATOLOGY 2006;44:195-204.)

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confidence: 99%

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Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport

et al. 2006

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“…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%

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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“…This gene, which encodes a P-type ATPase, is located on human chromosome 18 and is also mutated in the milder phenotype, benign recurrent intrahepatic cholestasis type 1 (BRIC1) and in Greenland familial cholestasis [6,12,13]. FIC1 protein is located on the canalicular membrane of the hepatocyte but within the liver it is mainly expressed in cholangiocytes [14][15][16]. The function of this P-type ATPase is unknown but it could be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phosphatidylethanolamine on the inner leaflet of the plasma membrane in comparison of the outer leaflet [6,14].…”

Section: Pficmentioning

confidence: 99%

Progressive Familial Intrahepatic Cholestasis

Jacquemin

2000

Clinics in Liver Disease

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FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte

Cited by 122 publications

References 28 publications

Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport

Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport

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

Progressive Familial Intrahepatic Cholestasis

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