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

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

doi:10.15252/emmm.201707860

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

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^*

^*Corresponding author for this work

Medicine and Health

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

27 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1696-1710
Number of pages	15
Journal	EMBO Molecular Medicine
Volume	9
Issue number	12
DOIs	https://doi.org/10.15252/emmm.201707860
Publication status	Published - Dec 2017

Bibliographical note

Funding Information:
This work was supported by the Medical Research Council (MRC; KPH, MR/ J003352/1 & MR/P023541/1; KM and VSA are MRC Clinical Training Fellows; SR is a KRUK Clinical Training Fellow); the Manchester Biomedical Research Centre and the Wellcome Trust (NAH, WT088566MA). The Core Histology Facility at the University of Manchester is acknowledged for their technical help and support. We acknowledge technical assistance from Kara Simpson.

Funding Information:
This work was supported by the Medical Research Council (MRC; KPH, MR/J003352/1 & MR/P023541/1; KM and VSA are MRC Clinical Training Fellows; SR?is a KRUK Clinical Training Fellow); the Manchester Biomedical Research Centre and the Wellcome Trust (NAH, WT088566MA). The Core Histology Facility at the University of Manchester is acknowledged for their technical help and support. We acknowledge technical assistance from Kara Simpson.

Publisher Copyright:
© 2017 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

extracellular matrix
hepatic stellate cells
liver fibrosis
SOX9
YAP1

ASJC Scopus subject areas

Molecular Medicine

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10.15252/emmm.201707860

Cite this

Athwal, V. S., Pritchett, J., Llewellyn, J., Martin, K., Camacho, E., Raza, S. M. A., Phythian-Adams, A., Birchall, L. J., Mullan, A. F., Su, K., Pearmain, L., Dolman, G., Zaitoun, A. M., Friedman, S. L., MacDonald, A., Irving, W. L., Guha, I. N., Hanley, N. A., & Piper Hanley, K. (2017). SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis. EMBO Molecular Medicine, 9(12), 1696-1710. https://doi.org/10.15252/emmm.201707860

@article{325f68689367455dbadefa08809da3eb,

title = "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 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.",

keywords = "extracellular matrix, hepatic stellate cells, liver fibrosis, SOX9, YAP1",

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

note = "Funding Information: This work was supported by the Medical Research Council (MRC; KPH, MR/ J003352/1 & MR/P023541/1; KM and VSA are MRC Clinical Training Fellows; SR is a KRUK Clinical Training Fellow); the Manchester Biomedical Research Centre and the Wellcome Trust (NAH, WT088566MA). The Core Histology Facility at the University of Manchester is acknowledged for their technical help and support. We acknowledge technical assistance from Kara Simpson. Funding Information: This work was supported by the Medical Research Council (MRC; KPH, MR/J003352/1 & MR/P023541/1; KM and VSA are MRC Clinical Training Fellows; SR?is a KRUK Clinical Training Fellow); the Manchester Biomedical Research Centre and the Wellcome Trust (NAH, WT088566MA). The Core Histology Facility at the University of Manchester is acknowledged for their technical help and support. We acknowledge technical assistance from Kara Simpson. Publisher Copyright: {\textcopyright} 2017 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2017",

month = dec,

doi = "10.15252/emmm.201707860",

language = "English",

volume = "9",

pages = "1696--1710",

journal = "EMBO Molecular Medicine",

issn = "1757-4676",

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}

Athwal, VS, Pritchett, J, Llewellyn, J, Martin, K, Camacho, E, Raza, SMA, Phythian-Adams, A, Birchall, LJ, Mullan, AF, Su, K, Pearmain, L, Dolman, G, Zaitoun, AM, Friedman, SL, MacDonald, A, Irving, WL, Guha, IN, Hanley, NA & Piper Hanley, K 2017, 'SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis', EMBO Molecular Medicine, vol. 9, no. 12, pp. 1696-1710. https://doi.org/10.15252/emmm.201707860

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

AU - Athwal, Varinder S.

AU - Pritchett, James

AU - Llewellyn, Jessica

AU - Martin, Katherine

AU - Camacho, Elizabeth

AU - Raza, Sayyid M.A.

AU - Phythian-Adams, Alexander

AU - Birchall, Lindsay J.

AU - Mullan, Aoibheann F.

AU - Su, Kim

AU - Pearmain, Laurence

AU - Dolman, Grace

AU - Zaitoun, Abed M.

AU - Friedman, Scott L.

AU - MacDonald, Andrew

AU - Irving, William L.

AU - Guha, Indra N.

AU - Hanley, Neil A.

AU - Piper Hanley, Karen

N1 - Funding Information: This work was supported by the Medical Research Council (MRC; KPH, MR/ J003352/1 & MR/P023541/1; KM and VSA are MRC Clinical Training Fellows; SR is a KRUK Clinical Training Fellow); the Manchester Biomedical Research Centre and the Wellcome Trust (NAH, WT088566MA). The Core Histology Facility at the University of Manchester is acknowledged for their technical help and support. We acknowledge technical assistance from Kara Simpson. Funding Information: This work was supported by the Medical Research Council (MRC; KPH, MR/J003352/1 & MR/P023541/1; KM and VSA are MRC Clinical Training Fellows; SR?is a KRUK Clinical Training Fellow); the Manchester Biomedical Research Centre and the Wellcome Trust (NAH, WT088566MA). The Core Histology Facility at the University of Manchester is acknowledged for their technical help and support. We acknowledge technical assistance from Kara Simpson. Publisher Copyright: © 2017 The Authors. Published under the terms of the CC BY 4.0 license

PY - 2017/12

Y1 - 2017/12

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 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.

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 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.

KW - extracellular matrix

KW - hepatic stellate cells

KW - liver fibrosis

KW - SOX9

KW - YAP1

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DO - 10.15252/emmm.201707860

M3 - Article

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AN - SCOPUS:85032994208

SN - 1757-4676

VL - 9

SP - 1696

EP - 1710

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 12

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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