Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells

Cohn, Jonathan; Strong, Theresa V.; Picciotto, Marina; Nairn, Angus C.; Collins, Francis S.; Fitz, John

doi:10.1016/0016-5085(93)91085-v

Cited by 334 publications

(186 citation statements)

References 27 publications

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“…According to this hypothesis, the absence of ATP8B1 putative translocase activity would impede the bilayer lipid asymmetry required for the activity of membrane-associated proteins, such as BSEP at the canalicular membrane of hepatocytes, or ASBT at the apical membrane of enterocytes. 34 An important new observation in this study is that CFTR, a gene expressed exclusively in cholangiocytes within the liver, 35,36 was downregulated selectively in patients with PFIC1. In the patient with biliary atresia, intense ductular reaction was associated with increased hepatic mRNA levels of CFTR, as previously reported in experimental bile duct obstruction.…”

Section: Discussionmentioning

confidence: 60%

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: Discussionmentioning

confidence: 60%

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

et al. 2006

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“…Moreover, the distribution of WNK1 expression is notable for its overlap with tissues that show pathology or physiologic defects in cystic fibrosis because of loss of the CFTR gene product (23)(24)(25)(26)(27)(28). These abnormalities in cystic fibrosis include defective Cl Ϫ absorption in sweat ducts (24), impaired pancreatic function caused by inadequate ductal HCO 3 Ϫ secretion with sludging of secretions in exocrine ducts (25), male sterility caused by obstruction and atrophy in the distal epididymis (26), hepatic fibrosis͞cirrhosis caused by inspissated biliary secretions (27), meconium ileus with distal intestinal impaction caused by defective Cl Ϫ transport and abnormal electrolyte absorption in the colon (28), and occasional cases of cholelithiasis caused by deranged gallbladder salt homeostasis (29).…”

Section: Discussionmentioning

confidence: 99%

WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl ⁻ -transporting epithelia

Choate

Kahle²,

Wilson³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

126

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Mutations in WNK1 and WNK4, genes encoding members of a novel family of serine-threonine kinases, have recently been shown to cause pseudohypoaldosteronism type II (PHAII), an autosomal dominant disorder featuring hypertension, hyperkalemia, and renal tubular acidosis. The localization of these kinases in the distal nephron and the Cl ؊ dependence of these phenotypes suggest that these mutations increase renal Cl ؊ reabsorption. Although WNK4 expression is limited to the kidney, WNK1 is expressed in many tissues. We have examined the distribution of WNK1 in these extrarenal tissues. Immunostaining using WNK1-specific antibodies demonstrated that WNK1 is not present in all cell types; rather, it is predominantly localized in polarized epithelia, including those lining the lumen of the hepatic biliary ducts, pancreatic ducts, epididymis, sweat ducts, colonic crypts, and gallbladder. WNK1 is also found in the basal layers of epidermis and throughout the esophageal epithelium. The subcellular localization of WNK1 varies among these epithelia. WNK1 is cytoplasmic in kidney, colon, gallbladder, sweat duct, skin, and esophagus; in contrast, it localizes to the lateral membrane in bile ducts, pancreatic ducts, and epididymis. These epithelia are all notable for their prominent role in Cl ؊ flux. Moreover, these sites largely coincide with those involved in the pathology of cystic fibrosis, a disease characterized by deranged epithelial Cl ؊ flux. Together with the known pathophysiology of PHAII, these findings suggest that WNK1 plays a general role in the regulation of epithelial Cl ؊ flux, a finding that suggests the potential of new approaches to the selective modulation of these processes.protein-serine-threonine kinases ͉ ion transport ͉ cystic fibrosis ͉ medical genetics

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“…The binding and modulation of CFTR by EBP50/E3KARP is of specific interest because intrahepatic bile ducts express CFTR and cAMP-induced fluid, HCO 3 Ϫ and Cl Ϫ secretion is primarily the consequence of CFTR Cl Ϫ channel activation. 43,44 Accordingly, definition of specific functional interactions between EBP50/ E3KARP and CFTR is likely to broaden our understanding of ductular secretion and provide mechanistic insights into cholestatic liver diseases of ductular origin. A dominant-negative strategy involving the expression of the PDZ1 domain of EBP50, the preferential binding site for CFTR, was utilized.…”

Section: Discussionmentioning

confidence: 99%

Ezrin–Radixin–Moesin-Binding Phosphoprotein 50 Is Expressed At the Apical Membrane of Rat Liver Epithelia

et al. 2001

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Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells

Cited by 334 publications

References 27 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

WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl ⁻ -transporting epithelia

Ezrin–Radixin–Moesin-Binding Phosphoprotein 50 Is Expressed At the Apical Membrane of Rat Liver Epithelia

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Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells

Cited by 334 publications

References 27 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

WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl − -transporting epithelia

Ezrin–Radixin–Moesin-Binding Phosphoprotein 50 Is Expressed At the Apical Membrane of Rat Liver Epithelia

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WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl ⁻ -transporting epithelia