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

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

doi:10.15252/emmm.201707860

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	EMBO Molecular Medicine
Early online date	6 Nov 2017
DOIs	https://doi.org/10.15252/emmm.201707860
Publication status	Published - 2017

Keywords

SOX9
YAP1
Liver fibrosis
Extracellular matrix
hepatic stellate cells

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Athwal, V., Pritchett, J., Llewellyn, J., Martin, K., Camacho, E., Raza, S., Phythian-Adams, A., Birchall, L., Mullan, A., Su, K., Pearmain, L., Dolman, G., Zaitoun, A. M., Friedman, S., MacDonald, A., Irving, W. L., Guha, I. N., Hanley, N., & Piper Hanley, K. (2017). SOX9 predicts progression towards cirrhosis in patients while its loss protects against liver fibrosis. EMBO Molecular Medicine . https://doi.org/10.15252/emmm.201707860

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title = "SOX9 predicts progression towards 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 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.",

keywords = "SOX9, YAP1, Liver fibrosis, Extracellular matrix, hepatic stellate cells",

author = "Varinder Athwal and James Pritchett and Jessica Llewellyn and Katherine Martin and Elizabeth Camacho and Sayyid Raza and Alexander Phythian-Adams and Lindsay Birchall and Aoibheann Mullan and Kimberley Su and Laurence Pearmain and Grace Dolman and Zaitoun, {Abed M.} and Scott Friedman and Andrew MacDonald and Irving, {William L.} and Guha, {Indra N.} and Neil Hanley and {Piper Hanley}, Karen",

year = "2017",

doi = "10.15252/emmm.201707860",

language = "English",

journal = "EMBO Molecular Medicine ",

issn = "1757-4676",

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Athwal, V, Pritchett, J, Llewellyn, J, Martin, K, Camacho, E, Raza, S, Phythian-Adams, A, Birchall, L, Mullan, A, Su, K, Pearmain, L, Dolman, G, Zaitoun, AM, Friedman, S, MacDonald, A, Irving, WL, Guha, IN, Hanley, N & Piper Hanley, K 2017, 'SOX9 predicts progression towards cirrhosis in patients while its loss protects against liver fibrosis', EMBO Molecular Medicine . https://doi.org/10.15252/emmm.201707860

TY - JOUR

T1 - SOX9 predicts progression towards cirrhosis in patients while its loss protects against liver fibrosis

AU - Athwal, Varinder

AU - Pritchett, James

AU - Llewellyn, Jessica

AU - Martin, Katherine

AU - Camacho, Elizabeth

AU - Raza, Sayyid

AU - Phythian-Adams, Alexander

AU - Birchall, Lindsay

AU - Mullan, Aoibheann

AU - Su, Kimberley

AU - Pearmain, Laurence

AU - Dolman, Grace

AU - Zaitoun, Abed M.

AU - Friedman, Scott

AU - MacDonald, Andrew

AU - Irving, William L.

AU - Guha, Indra N.

AU - Hanley, Neil

AU - Piper Hanley, Karen

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - SOX9

KW - YAP1

KW - Liver fibrosis

KW - Extracellular matrix

KW - hepatic stellate cells

U2 - 10.15252/emmm.201707860

DO - 10.15252/emmm.201707860

M3 - Article

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

ER -

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

Abstract

Keywords

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