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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2019-07-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/12/7/dmm038810 |
| _version_ | 1818257938523881472 |
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| author | Andrea Villar-Lorenzo Patricia Rada Esther Rey Patricia Marañón Ana I. Arroba Beatriz Santamaría Jorge Sáiz Francisco J. Rupérez Coral Barbas Carmelo García-Monzón Ángela M. Valverde Águeda González-Rodríguez |
| author_facet | Andrea Villar-Lorenzo Patricia Rada Esther Rey Patricia Marañón Ana I. Arroba Beatriz Santamaría Jorge Sáiz Francisco J. Rupérez Coral Barbas Carmelo García-Monzón Ángela M. Valverde Águeda González-Rodríguez |
| author_sort | Andrea Villar-Lorenzo |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-12T17:51:36Z |
| format | Article |
| id | doaj.art-b3286c416e784091b598f81ae14865c5 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-12T17:51:36Z |
| publishDate | 2019-07-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-b3286c416e784091b598f81ae14865c52022-12-22T00:16:47ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-07-0112710.1242/dmm.038810038810Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injuryAndrea Villar-Lorenzo0Patricia Rada1Esther Rey2Patricia Marañón3Ana I. Arroba4Beatriz Santamaría5Jorge Sáiz6Francisco J. Rupérez7Coral Barbas8Carmelo García-Monzón9Ángela M. Valverde10Águeda González-Rodríguez11 Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain Unidad de Investigación Hepática, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, 28009 Madrid, Spain Unidad de Investigación Hepática, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, 28009 Madrid, Spain Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Boadilla del Monte, 28668, Madrid, Spain Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Boadilla del Monte, 28668, Madrid, Spain Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Boadilla del Monte, 28668, Madrid, Spain Unidad de Investigación Hepática, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, 28009 Madrid, Spain Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain Unidad de Investigación Hepática, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, 28009 Madrid, Spain 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.http://dmm.biologists.org/content/12/7/dmm038810IRS2FibrosisBile acidsCholestatic injuryHepatic stellate cellsIGF1 |
| spellingShingle | Andrea Villar-Lorenzo Patricia Rada Esther Rey Patricia Marañón Ana I. Arroba Beatriz Santamaría Jorge Sáiz Francisco J. Rupérez Coral Barbas Carmelo García-Monzón Ángela M. Valverde Águeda González-Rodríguez Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury Disease Models & Mechanisms IRS2 Fibrosis Bile acids Cholestatic injury Hepatic stellate cells IGF1 |
| 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 | IRS2 Fibrosis Bile acids Cholestatic injury Hepatic stellate cells IGF1 |
| url | http://dmm.biologists.org/content/12/7/dmm038810 |
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