MedicGo
Impaired Redox and Protein Homeostasis as Risk Factors and Therapeutic Targets in Toxin-Induced Biliary Atresia.
Metadata
Journalgastroenterology17.373Date
2020 Jun 04
4 months ago
Type
Journal Article
Volume
2020-Sep / 159 : 1068-1084.e2
Author
Zhao X 1, Lorent K 1, Escobar-Zarate D 1, Rajagopalan R 2, Loomes KM 3, Gillespie K 4, Mesaros C 4, Estrada MA 5, Blair IA 4, Winkler JD 5, Spinner NB 3, Devoto M 6, Pack M 7
Affiliation
  • 2. Division of Genomic Diagnostics, Department of Pathology, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
  • 3. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
  • 4. Department of System Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 5. Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 6. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Departments of Pediatrics and of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Translational and Precision Medicine, University La Sapienza, Rome, Italy.
  • 7. Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: [email protected]
Doi
PMIDMESH
Abstract
BACKGROUND & AIMS: Extrahepatic biliary atresia (BA) is a pediatric liver disease with no approved medical therapy. Recent studies using human samples and experimental modeling suggest that glutathione redox metabolism and heterogeneity play a role in disease pathogenesis. We sought to dissect the mechanistic basis of liver redox variation and explore how other stress responses affect cholangiocyte injury in BA.
METHODS: We performed quantitative in situ hepatic glutathione redox mapping in zebrafish larvae carrying targeted mutations in glutathione metabolism genes and correlated these findings with sensitivity to the plant-derived BA-linked toxin biliatresone. We also determined whether genetic disruption of HSP90 protein quality control pathway genes implicated in human BA altered biliatresone toxicity in zebrafish and human cholangiocytes. An in vivo screening of a known drug library was performed to identify novel modifiers of cholangiocyte injury in the zebrafish experimental BA model, with subsequent validation.
RESULTS: Glutathione metabolism gene mutations caused regionally distinct changes in the redox potential of cholangiocytes that differentially sensitized them to biliatresone. Disruption of human BA-implicated HSP90 pathway genes sensitized zebrafish and human cholangiocytes to biliatresone-induced injury independent of glutathione. Phosphodiesterase-5 inhibitors and other cyclic guanosine monophosphate signaling activators worked synergistically with the glutathione precursor N-acetylcysteine in preventing biliatresone-induced injury in zebrafish and human cholangiocytes. Phosphodiesterase-5 inhibitors enhanced proteasomal degradation and required intact HSP90 chaperone.
CONCLUSION: Regional variation in glutathione metabolism underlies sensitivity to the biliary toxin biliatresone and may account for the reported association between BA transplant-free survival and glutathione metabolism gene expression. Human BA can be causatively linked to genetic modulation of protein quality control. Combined treatment with N-acetylcysteine and cyclic guanosine monophosphate signaling enhancers warrants further investigation as therapy for BA.
Keywords: Cholestasis Chronic Liver Disease Glutathione Metabolism
Fav
Like
Download
Share
Export
Cite
17.4
Gastroenterologygastroenterology
Metadata
LocationUnited States
FromW B SAUNDERS CO-ELSEVIER INC

No Data

© 2017 - 2020 Medicgo
Powered by some medical students