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Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury

Insulin receptor substrate 2 (IRS2) is a key downstream mediator of insulin and insulin-like growth factor 1 (IGF1) signalling pathways and plays a major role in liver metabolism. The aim of this study was to investigate whether IRS2 had an impact on the hepatic fibrotic process associated with chol...

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Autores principales: Villar-Lorenzo, Andrea, Rada, Patricia, Rey, Esther, Marañón, Patricia, Arroba, Ana I., Santamaría, Beatriz, Sáiz, Jorge, Rupérez, Francisco J., Barbas, Coral, García-Monzón, Carmelo, Valverde, Ángela M., González-Rodríguez, Águeda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679376/
https://www.ncbi.nlm.nih.gov/pubmed/31262748
http://dx.doi.org/10.1242/dmm.038810
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author Villar-Lorenzo, Andrea
Rada, Patricia
Rey, Esther
Marañón, Patricia
Arroba, Ana I.
Santamaría, Beatriz
Sáiz, Jorge
Rupérez, Francisco J.
Barbas, Coral
García-Monzón, Carmelo
Valverde, Ángela M.
González-Rodríguez, Águeda
author_facet Villar-Lorenzo, Andrea
Rada, Patricia
Rey, Esther
Marañón, Patricia
Arroba, Ana I.
Santamaría, Beatriz
Sáiz, Jorge
Rupérez, Francisco J.
Barbas, Coral
García-Monzón, Carmelo
Valverde, Ángela M.
González-Rodríguez, Águeda
author_sort Villar-Lorenzo, Andrea
collection PubMed
description Insulin receptor substrate 2 (IRS2) is a key downstream mediator of insulin and insulin-like growth factor 1 (IGF1) signalling pathways and plays a major role in liver metabolism. The aim of this study was to investigate whether IRS2 had an impact on the hepatic fibrotic process associated with cholestatic injury. Bile duct ligation (BDL) was performed in wild-type (WT) and Irs2-deficient (IRS2KO) female mice. Histological and biochemical analyses, together with fibrogenic and inflammatory responses were evaluated in livers from mice at 3, 7 and 28 days following BDL. We also explored whether activation of human hepatic stellate cells (HSCs) induced by IGF1 was modulated by IRS2. IRS2KO mice displayed reduced disruption of liver histology, such hepatocyte damage and excess deposition of extracellular matrix components, compared with WT mice at 3 and 7 days post-BDL. However, no histological differences between genotypes were found at 28 days post-BDL. The less pro-inflammatory profile of bile acids accumulated in the gallbladder of IRS2KO mice after BDL corresponded with the reduced expression of pro-inflammatory markers in these mice. Stable silencing of IRS2 or inhibition of ERK1/2 reduced the activation of human LX2 cells and also reduced induction of MMP9 upon IGF1 stimulation. Furthermore, hepatic MMP9 expression was strongly induced after BDL in WT mice, but only a slight increase was found in mice lacking IRS2. Our results have unravelled the signalling pathway mediated by IGF1R–IRS2–ERK1/2–MMP9 as a key axis in regulating HSC activation, which might be therapeutically relevant for targeting liver fibrosis.
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spelling pubmed-66793762019-08-12 Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury Villar-Lorenzo, Andrea Rada, Patricia Rey, Esther Marañón, Patricia Arroba, Ana I. Santamaría, Beatriz Sáiz, Jorge Rupérez, Francisco J. Barbas, Coral García-Monzón, Carmelo Valverde, Ángela M. González-Rodríguez, Águeda Dis Model Mech Research Article Insulin receptor substrate 2 (IRS2) is a key downstream mediator of insulin and insulin-like growth factor 1 (IGF1) signalling pathways and plays a major role in liver metabolism. The aim of this study was to investigate whether IRS2 had an impact on the hepatic fibrotic process associated with cholestatic injury. Bile duct ligation (BDL) was performed in wild-type (WT) and Irs2-deficient (IRS2KO) female mice. Histological and biochemical analyses, together with fibrogenic and inflammatory responses were evaluated in livers from mice at 3, 7 and 28 days following BDL. We also explored whether activation of human hepatic stellate cells (HSCs) induced by IGF1 was modulated by IRS2. IRS2KO mice displayed reduced disruption of liver histology, such hepatocyte damage and excess deposition of extracellular matrix components, compared with WT mice at 3 and 7 days post-BDL. However, no histological differences between genotypes were found at 28 days post-BDL. The less pro-inflammatory profile of bile acids accumulated in the gallbladder of IRS2KO mice after BDL corresponded with the reduced expression of pro-inflammatory markers in these mice. Stable silencing of IRS2 or inhibition of ERK1/2 reduced the activation of human LX2 cells and also reduced induction of MMP9 upon IGF1 stimulation. Furthermore, hepatic MMP9 expression was strongly induced after BDL in WT mice, but only a slight increase was found in mice lacking IRS2. Our results have unravelled the signalling pathway mediated by IGF1R–IRS2–ERK1/2–MMP9 as a key axis in regulating HSC activation, which might be therapeutically relevant for targeting liver fibrosis. The Company of Biologists Ltd 2019-07-01 2019-07-16 /pmc/articles/PMC6679376/ /pubmed/31262748 http://dx.doi.org/10.1242/dmm.038810 Text en © 2019. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Villar-Lorenzo, Andrea
Rada, Patricia
Rey, Esther
Marañón, Patricia
Arroba, Ana I.
Santamaría, Beatriz
Sáiz, Jorge
Rupérez, Francisco J.
Barbas, Coral
García-Monzón, Carmelo
Valverde, Ángela M.
González-Rodríguez, Águeda
Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury
title Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury
title_full Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury
title_fullStr Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury
title_full_unstemmed Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury
title_short Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury
title_sort insulin receptor substrate 2 (irs2) deficiency delays liver fibrosis associated with cholestatic injury
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679376/
https://www.ncbi.nlm.nih.gov/pubmed/31262748
http://dx.doi.org/10.1242/dmm.038810
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