Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis
Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of...
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Elsevier
2018-01-01
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Series: | Molecular Metabolism |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877817306853 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Águeda González-Rodríguez M. Pilar Valdecantos Patricia Rada Annalisa Addante Inés Barahona Esther Rey Virginia Pardo Laura Ruiz Laura M. Laiglesia María J. Moreno-Aliaga Carmelo García-Monzón Aránzazu Sánchez Ángela M. Valverde |
spellingShingle |
Águeda González-Rodríguez M. Pilar Valdecantos Patricia Rada Annalisa Addante Inés Barahona Esther Rey Virginia Pardo Laura Ruiz Laura M. Laiglesia María J. Moreno-Aliaga Carmelo García-Monzón Aránzazu Sánchez Ángela M. Valverde Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis Molecular Metabolism |
author_facet |
Águeda González-Rodríguez M. Pilar Valdecantos Patricia Rada Annalisa Addante Inés Barahona Esther Rey Virginia Pardo Laura Ruiz Laura M. Laiglesia María J. Moreno-Aliaga Carmelo García-Monzón Aránzazu Sánchez Ángela M. Valverde |
author_sort |
Águeda González-Rodríguez |
title |
Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis |
title_short |
Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis |
title_full |
Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis |
title_fullStr |
Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis |
title_full_unstemmed |
Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis |
title_sort |
dual role of protein tyrosine phosphatase 1b in the progression and reversion of non-alcoholic steatohepatitis |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2018-01-01 |
description |
Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). Methods: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2–7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. Results: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. Conclusions: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD. Keywords: PTP1B, Steatosis, Steatohepatitis, Inflammation, Oval cells |
url |
http://www.sciencedirect.com/science/article/pii/S2212877817306853 |
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doaj-2a3010ee6fed43bfbd8571c8dc1c951a2020-11-24T21:32:44ZengElsevierMolecular Metabolism2212-87782018-01-017132146Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitisÁgueda González-Rodríguez0M. Pilar Valdecantos1Patricia Rada2Annalisa Addante3Inés Barahona4Esther Rey5Virginia Pardo6Laura Ruiz7Laura M. Laiglesia8María J. Moreno-Aliaga9Carmelo García-Monzón10Aránzazu Sánchez11Ángela M. Valverde12Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, 28009 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; Corresponding author. Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, 28009 Madrid, Spain. Fax: +34 915854401.Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos IIII, 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos IIII, 28029 Madrid, SpainDepartamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos IIII, 28029 Madrid, SpainHospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, 28009 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos IIII, 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos IIII, 28029 Madrid, SpainDepartmento de Nutrición, Ciencias de la Alimentación y Fisiología/Centro de Investigación en Nutrición, Universidad de Navarra, 31008 Pamplona, SpainDepartmento de Nutrición, Ciencias de la Alimentación y Fisiología/Centro de Investigación en Nutrición, Universidad de Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, SpainHospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, 28009 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, SpainDepartamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos IIII, 28029 Madrid, Spain; Corresponding author. Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain.Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). Methods: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2–7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. Results: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. Conclusions: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD. Keywords: PTP1B, Steatosis, Steatohepatitis, Inflammation, Oval cellshttp://www.sciencedirect.com/science/article/pii/S2212877817306853 |