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SOX9 predicts progression towards cirrhosis in patients while its loss protects against liver fibrosis

Athwal, Varinder S.; Pritchett, James; Llewellyn, Jessica; Martin, Katherine; Camacho, Elizabeth; Raza, Sayyid M.A.; Phythian-Adams, Alexander; Birchall, Lindsay J.; Mullan, Aoibheann F.; Su, Kim; Pearmain, Laurence; Dolman, Grace; Zaitoun, Abed M.; Friedman, Scott L.; MacDonald, Andrew; Irving, William L.; Guha, Indra N.; Hanley, Neil A.; Hanley, Karen Piper

Authors

Varinder S. Athwal

James Pritchett

Jessica Llewellyn

Katherine Martin

Elizabeth Camacho

Sayyid M.A. 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



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 towards cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, 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.

Journal Article Type Article
Journal EMBO Molecular Medicine
Print ISSN 1757-4676
Electronic ISSN 1757-4684
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 9
Issue 12
APA6 Citation Athwal, V. S., Pritchett, J., Llewellyn, J., Martin, K., Camacho, E., Raza, S. M., …Hanley, K. P. (in press). SOX9 predicts progression towards cirrhosis in patients while its loss protects against liver fibrosis. EMBO Molecular Medicine, 9(12), https://doi.org/10.15252/emmm.201707860
DOI https://doi.org/10.15252/emmm.201707860
Keywords SOX9; YAP1; Liver fibrosis; Extracellular matrix; Hepatic stellate cells
Publisher URL http://embomolmed.embopress.org/content/early/2017/11/06/emmm.201707860
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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