β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction
Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of β-cate...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-10-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/71310 |
| _version_ | 1811253407370969088 |
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| author | Shikai Hu Jacquelyn O Russell Silvia Liu Catherine Cao Jackson McGaughey Ravi Rai Karis Kosar Junyan Tao Edward Hurley Minakshi Poddar Sucha Singh Aaron Bell Donghun Shin Reben Raeman Aatur D Singhi Kari Nejak-Bowen Sungjin Ko Satdarshan P Monga |
| author_facet | Shikai Hu Jacquelyn O Russell Silvia Liu Catherine Cao Jackson McGaughey Ravi Rai Karis Kosar Junyan Tao Edward Hurley Minakshi Poddar Sucha Singh Aaron Bell Donghun Shin Reben Raeman Aatur D Singhi Kari Nejak-Bowen Sungjin Ko Satdarshan P Monga |
| author_sort | Shikai Hu |
| collection | DOAJ |
| description | Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of β-catenin, one with β-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived β-catenin-positive hepatocytes and resolution of injury. KO1 showed persistent loss of β-catenin, NF-κB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of β-catenin, NFκB, and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or β-catenin led to NF-κB activation, DR, and inflammation. Thus, we report a novel β-catenin-NFκB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF. |
| first_indexed | 2024-04-12T16:50:28Z |
| format | Article |
| id | doaj.art-01ba755c7dab41ab8470c5fde355f0f3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:50:28Z |
| publishDate | 2021-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-01ba755c7dab41ab8470c5fde355f0f32022-12-22T03:24:24ZengeLife Sciences Publications LtdeLife2050-084X2021-10-011010.7554/eLife.71310β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reactionShikai Hu0Jacquelyn O Russell1Silvia Liu2Catherine Cao3Jackson McGaughey4Ravi Rai5Karis Kosar6Junyan Tao7Edward Hurley8Minakshi Poddar9Sucha Singh10Aaron Bell11Donghun Shin12https://orcid.org/0000-0002-7975-9014Reben Raeman13Aatur D Singhi14Kari Nejak-Bowen15Sungjin Ko16Satdarshan P Monga17https://orcid.org/0000-0002-8437-3378School of Medicine, Tsinghua University, Beijing, China; Department of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United States; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pediatrics, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesPittsburgh Liver Research Center, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United States; Department of Developmental Biology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United States; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United States; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United States; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United States; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United States; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United States; Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United StatesExpansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of β-catenin, one with β-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived β-catenin-positive hepatocytes and resolution of injury. KO1 showed persistent loss of β-catenin, NF-κB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of β-catenin, NFκB, and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or β-catenin led to NF-κB activation, DR, and inflammation. Thus, we report a novel β-catenin-NFκB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF.https://elifesciences.org/articles/71310ductular reactionbeta-cateninNF-κB cystic fibrosischolangiocytesliver fibrosis |
| spellingShingle | Shikai Hu Jacquelyn O Russell Silvia Liu Catherine Cao Jackson McGaughey Ravi Rai Karis Kosar Junyan Tao Edward Hurley Minakshi Poddar Sucha Singh Aaron Bell Donghun Shin Reben Raeman Aatur D Singhi Kari Nejak-Bowen Sungjin Ko Satdarshan P Monga β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction eLife ductular reaction beta-catenin NF-κB cystic fibrosis cholangiocytes liver fibrosis |
| title | β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction |
| title_full | β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction |
| title_fullStr | β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction |
| title_full_unstemmed | β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction |
| title_short | β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction |
| title_sort | β catenin nf κb cftr interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction |
| topic | ductular reaction beta-catenin NF-κB cystic fibrosis cholangiocytes liver fibrosis |
| url | https://elifesciences.org/articles/71310 |
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