SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis
Abstract Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation in vivo governing fibrotic...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201707860 |
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| author | Varinder S Athwal James Pritchett Jessica Llewellyn Katherine Martin Elizabeth Camacho Sayyid MA Raza Alexander Phythian‐Adams Lindsay J Birchall Aoibheann F Mullan Kim Su Laurence Pearmain Grace Dolman Abed M Zaitoun Scott L Friedman Andrew MacDonald William L Irving Indra N Guha Neil A Hanley Karen Piper Hanley |
| author_facet | Varinder S Athwal James Pritchett Jessica Llewellyn Katherine Martin Elizabeth Camacho Sayyid MA Raza Alexander Phythian‐Adams Lindsay J Birchall Aoibheann F Mullan Kim Su Laurence Pearmain Grace Dolman Abed M Zaitoun Scott L Friedman Andrew MacDonald William L Irving Indra N Guha Neil A Hanley Karen Piper Hanley |
| author_sort | Varinder S Athwal |
| collection | DOAJ |
| description | Abstract Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation in vivo governing fibrotic matrix deposition by liver myofibroblasts. This gap in understanding has hampered molecular predictions of disease severity and clinical progression and restricted targets for antifibrotic drug development. In this study, we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression toward cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, and improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic, and therapeutic targets in patients with liver fibrosis. |
| format | Article |
| id | doaj-art-7cb0b6d70b99433cb9c83340f10c12cf |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-7cb0b6d70b99433cb9c83340f10c12cf2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-11-019121696171010.15252/emmm.201707860SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosisVarinder S Athwal0James Pritchett1Jessica Llewellyn2Katherine Martin3Elizabeth Camacho4Sayyid MA Raza5Alexander Phythian‐Adams6Lindsay J Birchall7Aoibheann F Mullan8Kim Su9Laurence Pearmain10Grace Dolman11Abed M Zaitoun12Scott L Friedman13Andrew MacDonald14William L Irving15Indra N Guha16Neil A Hanley17Karen Piper Hanley18Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterSchool of Healthcare Science, Manchester Metropolitan UniversityDivision of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterCentre for Health Economics, Institute of Population Health, Faculty of Medical & Human Sciences, Manchester Academic Health Science Centre, University of ManchesterDivision of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterManchester Centre for Collaborative Inflammation Research, Faculty of Life Sciences, University of ManchesterDivision of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterNottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of NottinghamDepartment of Cellular Pathology, Nottingham Digestive Diseases Centre and National Institute of Health Research Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals NHS TrustDivision of Liver Diseases, Icahn School of Medicine at Mount SinaiManchester Centre for Collaborative Inflammation Research, Faculty of Life Sciences, University of ManchesterNottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of NottinghamNottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of NottinghamDivision of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of ManchesterAbstract Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation in vivo governing fibrotic matrix deposition by liver myofibroblasts. This gap in understanding has hampered molecular predictions of disease severity and clinical progression and restricted targets for antifibrotic drug development. In this study, we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression toward cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, and improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic, and therapeutic targets in patients with liver fibrosis.https://doi.org/10.15252/emmm.201707860extracellular matrixhepatic stellate cellsliver fibrosisSOX9YAP1 |
| spellingShingle | Varinder S Athwal James Pritchett Jessica Llewellyn Katherine Martin Elizabeth Camacho Sayyid MA Raza Alexander Phythian‐Adams Lindsay J Birchall Aoibheann F Mullan Kim Su Laurence Pearmain Grace Dolman Abed M Zaitoun Scott L Friedman Andrew MacDonald William L Irving Indra N Guha Neil A Hanley Karen Piper Hanley SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis EMBO Molecular Medicine extracellular matrix hepatic stellate cells liver fibrosis SOX9 YAP1 |
| title | SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis |
| title_full | SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis |
| title_fullStr | SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis |
| title_full_unstemmed | SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis |
| title_short | SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis |
| title_sort | sox9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis |
| topic | extracellular matrix hepatic stellate cells liver fibrosis SOX9 YAP1 |
| url | https://doi.org/10.15252/emmm.201707860 |
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