Abstract
Biliary atresia is a neonatal liver disease with extrahepatic bile duct obstruction and progressive liver fibrosis. The etiology and pathogenesis of the disease are unknown. We previously identified a plant toxin, biliatresone, responsible for biliary atresia in naturally-occurring animal models, that causes cholangiocyte destruction in in-vitro models. Decreases in reduced glutathione (GSH) mimic the effects of biliatresone, and agents that replenish cellular GSH ameliorate the effects of the toxin. The goals of this study were to define signaling pathways downstream of biliatresone that lead to cholangiocyte destruction and to determine their relationship to GSH. Using cholangiocyte culture and 3D cholangiocyte spheroid cultures, we found that biliatresone and decreases in GSH upregulated RhoU/Wrch1, a Wnt signaling family member, which then mediated an increase in Hey2 in the NOTCH signaling pathway, causing downregulation of the transcription factor Sox17. When these genes were up- or down-regulated, the biliatresone effect on spheroids was phenocopied, resulting in lumen obstruction. Biopsies of patients with biliary atresia demonstrated increased RhoU/Wrch1 and Hey2 expression in cholangiocytes. We present a novel pathway of cholangiocyte injury in a model of biliary atresia, which is relevant to human BA and may suggest potential future therapeutics.
| Original language | English |
|---|---|
| Article number | 7599 |
| Journal | Scientific Reports |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| State | Published - 5 May 2020 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2020, The Author(s).
Funding
We thank Sackler Faculty of Medicine, Microscopy core for imaging support. We thank Jeffrey Winkler (University of Pennsylvania) for synthesizing biliatresone. The study was supported in part by an Israel Science Foundation (ISF) grant 645/17 to O.W.-Z, grants from the Fred and Suzanne Biesecker Liver Center at the Children’s Hospital of Philadelphia to O.W.-Z. and R.G.W. and a grant from United States - Israel Binational Science Foundation 2017212 to O.W.-Z. and R.G.W., and National Institutes of Health grant R01 DK119290 to R.G.W. S.F. work was done as a part of post-doctoral studies in Tel-Aviv university, and was partially supported by Israel’s Ministry of Science and Technology (Yitzhak Navon Postdoc Fellowship). TROMAIII, K19 antibody was obtained from Developmental Studies Hybridoma Bank (DSHB).
| Funders | Funder number |
|---|---|
| Children’s Hospital of Philadelphia | |
| Israel’s Ministry of Science and Technology | |
| National Institutes of Health | |
| National Institute of Diabetes and Digestive and Kidney Diseases | R01DK119290 |
| United States - Israel Binational Agricultural Research and Development Fund | 2017212 |
| Israel Science Foundation | 645/17 |
