Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity

Chen, Fanglin; Ananthanarayanan, Meenakshisundaram; Emre, Sukru; Neimark, Ezequiel; Bull, Laura N.; Knisely, A. S.; Strautnieks, Sandra; Rj, Thompson; Magid, Margret S.; Gordon, Ronald E.; Balasubramanian, Niranjan; Suchy, Frederick J.; Shneider, Benjamin L.

doi:10.1053/j.gastro.2003.12.013

Cited by 184 publications

(149 citation statements)

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“…Previous studies have outlined putative functions of ATP8B1 in hepatocytes and in enterocytes. 5,13,14 In the present study, we provide evidence that cholangiocytes are a site of high endogenous expression of ATP8B1 in the liver and biliary tract. Furthermore, the ATP8B1 defect was associated with a downregulation in the expression of CFTR, a key player in the physiology of these cells.…”

Section: Discussionsupporting

confidence: 55%

“…12 It has been previously shown that loss of ATP8B1 in the ileum of patients with PFIC1 impaired FXR expression and activation, leading to an overexpression of ASBT, which would presumably cause intestinal bile salt hyperabsorption in these subjects. 13 Subsequently, it has been shown by another group that, in the liver from one patient with PFIC1, the expression of FXR and of FXR target genes including BSEP was reduced. 14 These findings have suggested that ATP8B1 deficiency could cause FXR deregulation at hepatic and intestinal levels.…”

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: Discussionsupporting

confidence: 55%

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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“…These modifications can last for a few days or weeks before liver failure or other serious liver injuries occur [5][6][7] . To halt the process of liver fibrosis, early intervention for cholestasis is critical.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

et al. 2014

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Aim: α-Naphthylisothiocyanate (ANIT) is a well-characterized cholestatic agent for rats. The aim of this study was to examine whether resveratrol could attenuate ANIT-induced acute cholestasis and liver injury in rats. Methods: SD rats were treated with resveratrol (15 or 30 mg/kg, ip) or a positive control drug ursodeoxycholic acid (100 mg/kg, po) for 5 consecutive days followed by a single dose of ANIT (60 mg/kg, po). Bile flow, and serum biochemical markers and bile constituents were measured 48 h after ANIT administration. Hepatic levels of oxidative repair enzymes (glutathione peroxidase, catalase and MnSOD), myeloperoxidase activity, TNF-α, IL-6, and ATP content, as well as the expression of liver transporter genes and proteins were assayed. Results: ANIT exposure resulted in serious cholestasis and liver injury, as shown by marked neutrophil infiltration in liver, dramatically increased serum levels of ALT, AST, GGT, ALP, TBA, TBIL, IBIL, and DBIL, and significantly decreased bile excretion and biliary output of GSH and HCO 3 -. ANIT significantly increased TNF-α and IL-6 release and myeloperoxidase activity, decreased mitochondrial biogenesis in liver, but had little effect on hepatic oxidative repair enzymes and ATP content. Furthermore, ANIT significantly decreased the expression of Mrp2, FXR, and Cyp7a1, markedly increased Mrp3 expression in liver. Pretreatment with resveratrol attenuated ANITinduced acute cholestasis and liver injury, and other pathological changes. Pretreatment with ursodeoxycholic acid was less effective. Conclusion: Resveratrol effectively attenuates ANIT-induced acute cholestasis and liver injury in rats, possibly through suppression of neutrophil infiltration, as well as upregulation of expression of hepatic transporters and enzymes, thus decreasing accumulation of bile acids.

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“…In 5 families only parental DNA was analysed. We have previously reported single mutations in 8 families 1,2,32 ; the second mutant allele is now identified in each. Clinical observations in 21 families have been reported previously 28,29,33 .…”

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confidence: 96%

Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 Families

et al. 2008

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BACKGROUND & AIMS:Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS: With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential. Abbreviations:ABC, ATP-binding cassette; AFP, α-fetoprotein; BSEP, bile salt export pump; CpG, cytosine-guanine; CC, cholangiocarcinoma; FIC1, familial intrahepatic cholestasis 1; γ-GT, γ-glutamyl transferase; HCC, hepatocellular carcinoma; IC, intracellular loop; MDR1, multidrug resistance protein 1; MDR3, multidrug resistance protein 3; MRP2, multidrug resistance-associated protein 2; NBF, nucleotide-binding fold; OLT, orthotopic liver transplantation; PEBD, partial external biliary diversion; PFIC, progressive familial intrahepatic cholestasis; PCR, polymerase chain reaction; RE, restriction endonuclease; SSCP, single-strand conformation polymorphism; TM, transmembrane domain; UDCA, ursodeoxycholic acid Acknowledgements We thank the families and the Children's Liver Disease Foundation for support and encouragement, and those who referred families for analysis, including Drs U Baumann, W Berquist, M de Vree, K Emerick, G Ferry, M Finegold, W Hardikar, S Horslen, R Houwen, R Jaffe, L Klomp, F Lacaille, K Mann, P McKiernan, H Sharp, R Sokol, E Sturm, L Szönyi, J Taminou, and J Watkins. We also thank Dr R Garcia-Kennedy for access...

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Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity

Cited by 184 publications

References 31 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

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 Families

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