Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury

Elena Arriazu; Xiaodong Ge; Tung-Ming Leung; Fernando Magdaleno; Aritz Lopategi; Yongke Lu; Naoto Kitamura; Raquel Urtasun; Neil Theise; Daniel J Antoine; Natalia Nieto

doi:10.1136/gutjnl-2015-310752

Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury

Elena Arriazu, Xiaodong Ge, Tung-Ming Leung, Fernando Magdaleno, Aritz Lopategi, Yongke Lu, Naoto Kitamura, Raquel Urtasun, Neil Theise, Daniel J Antoine, Natalia Nieto

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

Abstract

OBJECTIVE: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.

DESIGN AND RESULTS: Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn-/- mice. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K-pAkt1/2/3 pathway to upregulate collagen-I.

CONCLUSIONS: During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.

Original language	English
Pages (from-to)	1123-1137
Number of pages	15
Journal	Gut
Volume	66
Issue number	6
Early online date	12 May 2017
DOIs	https://doi.org/10.1136/gutjnl-2015-310752
Publication status	E-pub ahead of print - 12 May 2017

Keywords

Acetylation
Animals
Antibodies, Neutralizing
Carbon Tetrachloride
Case-Control Studies
Cell Nucleus
Cells, Cultured
Collagen Type I
Cytoplasm
Disease Progression
Gene Expression
HMGB1 Protein
Hepatic Stellate Cells
Hepatitis C, Chronic
Hepatocytes
Histone Deacetylase 1
Histone Deacetylase 2
Humans
Liver Cirrhosis
Mice
Mice, Knockout
Mice, Transgenic
NADPH Oxidases
Osteopontin
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
Receptor for Advanced Glycation End Products
Recombinant Proteins
Signal Transduction
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

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10.1136/gutjnl-2015-310752

Antoine D Signalling via the osteopontin...
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Cite this

@article{0726b7bad71c465b80621dea74e9e6a8,

title = "Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury",

abstract = "OBJECTIVE: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.DESIGN AND RESULTS: Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn-/- mice. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K-pAkt1/2/3 pathway to upregulate collagen-I.CONCLUSIONS: During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.",

keywords = "Acetylation, Animals, Antibodies, Neutralizing, Carbon Tetrachloride, Case-Control Studies, Cell Nucleus, Cells, Cultured, Collagen Type I, Cytoplasm, Disease Progression, Gene Expression, HMGB1 Protein, Hepatic Stellate Cells, Hepatitis C, Chronic, Hepatocytes, Histone Deacetylase 1, Histone Deacetylase 2, Humans, Liver Cirrhosis, Mice, Mice, Knockout, Mice, Transgenic, NADPH Oxidases, Osteopontin, Phosphatidylinositol 3-Kinase, Proto-Oncogene Proteins c-akt, Receptor for Advanced Glycation End Products, Recombinant Proteins, Signal Transduction, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural",

author = "Elena Arriazu and Xiaodong Ge and Tung-Ming Leung and Fernando Magdaleno and Aritz Lopategi and Yongke Lu and Naoto Kitamura and Raquel Urtasun and Neil Theise and Antoine, {Daniel J} and Natalia Nieto",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.",

year = "2017",

month = may,

day = "12",

doi = "10.1136/gutjnl-2015-310752",

language = "English",

volume = "66",

pages = "1123--1137",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "6",

}

TY - JOUR

T1 - Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury

AU - Arriazu, Elena

AU - Ge, Xiaodong

AU - Leung, Tung-Ming

AU - Magdaleno, Fernando

AU - Lopategi, Aritz

AU - Lu, Yongke

AU - Kitamura, Naoto

AU - Urtasun, Raquel

AU - Theise, Neil

AU - Antoine, Daniel J

AU - Nieto, Natalia

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PY - 2017/5/12

Y1 - 2017/5/12

N2 - OBJECTIVE: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.DESIGN AND RESULTS: Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn-/- mice. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K-pAkt1/2/3 pathway to upregulate collagen-I.CONCLUSIONS: During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.

AB - OBJECTIVE: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.DESIGN AND RESULTS: Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn-/- mice. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K-pAkt1/2/3 pathway to upregulate collagen-I.CONCLUSIONS: During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.

KW - Acetylation

KW - Animals

KW - Antibodies, Neutralizing

KW - Carbon Tetrachloride

KW - Case-Control Studies

KW - Cell Nucleus

KW - Cells, Cultured

KW - Collagen Type I

KW - Cytoplasm

KW - Disease Progression

KW - Gene Expression

KW - HMGB1 Protein

KW - Hepatic Stellate Cells

KW - Hepatitis C, Chronic

KW - Hepatocytes

KW - Histone Deacetylase 1

KW - Histone Deacetylase 2

KW - Humans

KW - Liver Cirrhosis

KW - Mice

KW - Mice, Knockout

KW - Mice, Transgenic

KW - NADPH Oxidases

KW - Osteopontin

KW - Phosphatidylinositol 3-Kinase

KW - Proto-Oncogene Proteins c-akt

KW - Receptor for Advanced Glycation End Products

KW - Recombinant Proteins

KW - Signal Transduction

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, N.I.H., Extramural

U2 - 10.1136/gutjnl-2015-310752

DO - 10.1136/gutjnl-2015-310752

M3 - Article

C2 - 26818617

VL - 66

SP - 1123

EP - 1137

JO - Gut

JF - Gut

SN - 0017-5749

IS - 6

ER -

Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury

Abstract

Keywords

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