Biliary Atresia in Children With Aberrations Involving Chromosome 11q

Rurarz, Małgorzata; Czubkowski, Piotr; Chrzanowska, Krystyna; Cielecka-Kuszyk, Joanna; Marczak, Aleksandra; Kamińska, Diana; Pawłowska, Joanna

doi:10.1097/mpg.0b013e31829e25b8

Cited by 5 publications

(3 citation statements)

References 8 publications

(8 reference statements)

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“…The etiology of BA is unknown, although epidemiological studies support an infection or toxin exposure, likely occurring prenatally, in the setting of genetic susceptibility . Our group recently identified an isoflavonoid called biliatresone that has been implicated in outbreaks of a BA‐like syndrome in Australian livestock and also causes selective EHBD destruction in zebrafish .…”

Section: Discussionmentioning

confidence: 99%

The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and SOX17

et al. 2016

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Biliary atresia, the most common indication for pediatric liver transplantation, is a fibrotic disease of unknown etiology affecting the extrahepatic bile ducts of newborns. The recently-described toxin biliatresone causes lumen obstruction in mouse cholangiocyte spheroids and represents a new model of biliary atresia. Our aim was to determine the cellular changes caused by biliatresone in mammalian cells that ultimately lead to biliary atresia and extra-hepatic fibrosis. We treated mouse cholangiocytes in 3D spheroid culture and neonatal extra-hepatic duct explants with biliatresone and compounds that regulate glutathione. We examined the effects of biliatresone on SOX17 levels, and determined the effects of Sox17 knockdown on cholangiocytes in 3D culture. We found that biliatresone caused disruption of cholangiocyte apical polarity and loss of monolayer integrity. Spheroids treated with biliatresone had increased permeability as shown by rhodamine efflux within 5 hours compared to untreated spheroids, which retained rhodamine for longer than 12 hours. Neonatal bile duct explants treated with the toxin showed lumen obstruction with increased subepithelial staining for α-smooth muscle actin and collagen, consistent with fibrosis. Biliatresone caused a rapid and transient decrease in glutathione, which was both necessary and sufficient to mediate its effects in cholangiocyte spheroid and bile duct explant systems. It also caused a significant decrease in in cholangiocyte levels of SOX17, and Sox17 knockdown in cholangiocyte spheroids mimicked the effects of biliatresone. Conclusion Biliatresone decreases glutathione and SOX17 in mouse cholangiocytes. In 3D cell systems, this leads to cholangiocyte monolayer damage and increased permeability and in extrahepatic bile duct explants it leads to disruption of the extra-hepatic biliary tree and subepithelial fibrosis. This mechanism may be important in understanding human biliary atresia.

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Section: Discussionmentioning

confidence: 99%

The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and SOX17

et al. 2016

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“…3 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. 4 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 5 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.…”

Section: Isolation and Biochemical Characterization Of Biliatresonementioning

confidence: 99%

“…Neither form of BA displays Mendelian inheritance, and most twin studies have shown nonconcordance, thus arguing against a single genetic determinant. Genome-wide association studies (GWAS) have led to identification of potential BA susceptibility loci on several different chromosomes, and a recent study suggested an association between BA risk and specific mitochondrial DNA haplogroups (3)(4)(5)(6). Unfortunately, none of the affected genes within these regions have been identified.…”

Section: Introductionmentioning

confidence: 99%

Identification of a plant isoflavonoid that causes biliary atresia

et al. 2015

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Biliary atresia (BA) is a rapidly progressive and destructive fibrotic disorder of unknown etiology affecting the extrahepatic biliary tree of neonates. Epidemiological studies suggest that an environmental factor, such as a virus or toxin, is the cause of the disease, although none have been definitively established. Several naturally occurring outbreaks of BA in Australian livestock have been associated with the ingestion of unusual plants by pregnant animals during drought conditions. We used a biliary secretion assay in zebrafish to isolate a previously undescribed isoflavonoid, biliatresone, from Dysphania species implicated in a recent BA outbreak. This compound caused selective destruction of the extrahepatic, but not intrahepatic, biliary system of larval zebrafish. A mutation that enhanced biliatresone toxicity mapped to a region of the zebrafish genome that has conserved synteny with an established human BA susceptibility locus. The toxin also caused loss of cilia in neonatal mouse extrahepatic cholangiocytes in culture and disrupted cell polarity and monolayer integrity in cholangiocyte spheroids. Together, these findings provide direct evidence that BA could be initiated by perinatal exposure to an environmental toxin.

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