Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1

Álvarez, Luis; Jara, Paloma; Sánchez-Sabaté, Elena; Hierro, Loreto; Larrauri, J; Diaz, Maria Carmen G.; Camarena, C.; Vega, A. de la; Frauca, E; López-Collazo, Eduardo; Lapunzina, Pablo

doi:10.1093/hmg/ddh261

Cited by 109 publications

(71 citation statements)

References 56 publications

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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%

“…8,27 Recently, two groups reported on decreased FXR mRNA levels in the liver and intestine of patients with PFIC1, with subsequent downregulation of BSEP mRNA in the liver, and upregulation of ASBT mRNA in the intestine. 13,14 Both groups have suggested that impaired ATP8B1 function resulted in reduced FXR expression and/or activity with subsequent impairment of canalicular and ileal bile salt transport, which would be causative for the cholestatic phenotype. Yet, in the present study, patients with PFIC1 as well as patients with other types of cholestatic diseases (PFIC2 and biliary atresia) showed reduced hepatic expression of FXR, suggesting that the drop in FXR levels is secondary to cholestasis.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…7,8,12,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][57][58][59] This study showed that some ABCB11 missense mutations were associated with splicing defects, most caused protein processing defects, and the two functionally analyzed showed a reduction in taurocholate transport. Additionally, the ability to modulate splicing and protein processing defects was examined; some mutations were amenable to such treatments.…”

Section: Discussionmentioning

confidence: 76%

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing #

et al. 2009

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The gene encoding the human bile salt export pump (BSEP), ABCB11, is mutated in several forms of intrahepatic cholestasis. Here we classified the majority (63) of known ABCB11 missense mutations and 21 single-nucleotide polymorphisms (SNPs) to determine whether they caused abnormal ABCB11 pre-messenger RNA splicing, abnormal processing of BSEP protein, or alterations in BSEP protein function. Using an in vitro minigene system to analyze splicing events, we found reduced wild-type splicing for 20 mutations/SNPs, with normal mRNA levels reduced to 5% or less in eight cases. The common ABCB11 missense mutation encoding D482G enhanced aberrant splicing, whereas the common SNP A1028A promoted exon skipping. Addition of exogenous splicing factors modulated several splicing defects. Of the mutants expressed in vitro in CHO-K1 cells, most appeared to be retained in the endoplasmic reticulum and degraded. A minority had BSEP levels similar to wild-type. The SNP variant A444 had reduced levels of protein compared with V444. Treatment with glycerol and incubation at reduced temperature overcame processing defects for several mutants, including E297G. Taurocholate transport by two assessed mutants, N490D and A570T, was reduced compared with wild-type. Conclusion: This work is a comprehensive analysis of 80% of ABCB11 missense mutations and singlenucleotide polymorphisms at pre-mRNA splicing and protein processing/functional levels. We show that aberrant pre-mRNA splicing occurs in a considerable number of cases, leading to reduced levels of normal mRNA. Thus, primary defects at either the protein or the mRNA level (or both) contribute significantly to BSEP deficiency. These results will help to develop mutation-specific therapies for children and adults suffering from intrahepatic cholestasis due to BSEP deficiency. (HEPATOLOGY 2009;49:553-567.)

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“…It plays an integral role in phospholipid translocation. Proposed mechanisms for cholestasis include reduced bile salt secretion due to farnesoid X receptor (FXR) downregulation and overloading of bile acids in hepatocytes due to bile salt export pump (BSEP) downregulation and increased bile acid synthesis within hepatocytes [61,62]. High expression of the ATP8B1 gene is also noted in the cholangiocytes, small bowel, kidney and pancreas and may account for the symptoms of diarrhoea and pancreatic insufficiency in PFIC1 patients.…”

Section: Genetic Cholestatic Disordersmentioning

confidence: 99%

The management of childhood liver diseases in adulthood

Joshi

Gupta

Samyn

et al. 2017

Journal of Hepatology

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SummaryAn increasing number of patients with childhood liver disease survive into adulthood. These young adults are now entering adult services and require ongoing management. Aetiologies can be divided into liver diseases that develop in young adults which present to adult hepatologists i.e., biliary atresia and Alagille syndrome or liver diseases that occur in children/adolescents and adults i.e., autoimmune hepatitis or Wilson's disease. To successfully manage these young adults, a dynamic and responsive transition service is essential. In this review, we aim to describe the successful components of a transition service highlighting the importance of self-management support and a multi-disciplinary approach. We will also review some of the liver specific aetiologies which are unique to young adults, offering an update on pathogenesis, management and outcomes. Ó

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Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1

Cited by 109 publications

References 56 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

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing #

The management of childhood liver diseases in adulthood

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