Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice
Objective: Non-alcoholic steatohepatitis (NASH) is characterized by a robust pro-inflammatory component at both hepatic and systemic levels together with a disease-specific gut microbiome signature. Protein tyrosine phosphatase 1 B (PTP1B) plays distinct roles in non-immune and immune cells, in the...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-05-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820300260 |
| _version_ | 1818821665058979840 |
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| author | Carmen Rubio Marta Puerto Juan J. García-Rodríquez Van B. Lu Irma García-Martínez Rosa Alén Patricia Sanmartín-Salinas M. Val Toledo-Lobo Jorge Saiz Javier Ruperez Coral Barbas Luis Menchén Fiona M. Gribble Frank Reimann Luis G. Guijarro Jose M. Carrascosa Ángela M. Valverde |
| author_facet | Carmen Rubio Marta Puerto Juan J. García-Rodríquez Van B. Lu Irma García-Martínez Rosa Alén Patricia Sanmartín-Salinas M. Val Toledo-Lobo Jorge Saiz Javier Ruperez Coral Barbas Luis Menchén Fiona M. Gribble Frank Reimann Luis G. Guijarro Jose M. Carrascosa Ángela M. Valverde |
| author_sort | Carmen Rubio |
| collection | DOAJ |
| description | Objective: Non-alcoholic steatohepatitis (NASH) is characterized by a robust pro-inflammatory component at both hepatic and systemic levels together with a disease-specific gut microbiome signature. Protein tyrosine phosphatase 1 B (PTP1B) plays distinct roles in non-immune and immune cells, in the latter inhibiting pro-inflammatory signaling cascades. In this study, we have explored the role of PTP1B in the composition of gut microbiota and gut barrier dynamics in methionine and choline-deficient (MCD) diet-induced NASH in mice. Methods: Gut features and barrier permeability were characterized in wild-type (PTP1B WT) and PTP1B-deficient knockout (PTP1B KO) mice fed a chow or methionine/choline-deficient (MCD) diet for 4 weeks. The impact of inflammation was studied in intestinal epithelial and enteroendocrine cells. The secretion of GLP-1 was evaluated in primary colonic cultures and plasma of mice. Results: We found that a shift in the gut microbiota shape, disruption of gut barrier function, higher levels of serum bile acids, and decreased circulating glucagon-like peptide (GLP)-1 are features during NASH. Surprisingly, despite the pro-inflammatory phenotype of global PTP1B-deficient mice, they were partly protected against the alterations in gut microbiota composition during NASH and presented better gut barrier integrity and less permeability under this pathological condition. These effects concurred with higher colonic mucosal inflammation, decreased serum bile acids, and protection against the decrease in circulating GLP-1 levels during NASH compared with their WT counterparts together with increased expression of GLP-2-sensitive genes in the gut. At the molecular level, stimulation of enteroendocrine STC-1 cells with a pro-inflammatory conditioned medium (CM) from lipopolysaccharide (LPS)-stimulated macrophages triggered pro-inflammatory signaling cascades that were further exacerbated by a PTP1B inhibitor. Likewise, the pro-inflammatory CM induced GLP-1 secretion in primary colonic cultures, an effect augmented by PTP1B inhibition. Conclusion: Altogether our results have unraveled a potential role of PTP1B in the gut–liver axis during NASH, likely mediated by increased sensitivity to GLPs, with potential therapeutic value. Keywords: NASH, PTP1B, Inflammation, Gut microbiota, GLP-1, GLP-2 |
| first_indexed | 2024-12-18T23:11:48Z |
| format | Article |
| id | doaj.art-e20f2ee3c18a474e88809eb466830a96 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-18T23:11:48Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-e20f2ee3c18a474e88809eb466830a962022-12-21T20:48:20ZengElsevierMolecular Metabolism2212-87782020-05-0135Impact of global PTP1B deficiency on the gut barrier permeability during NASH in miceCarmen Rubio0Marta Puerto1Juan J. García-Rodríquez2Van B. Lu3Irma García-Martínez4Rosa Alén5Patricia Sanmartín-Salinas6M. Val Toledo-Lobo7Jorge Saiz8Javier Ruperez9Coral Barbas10Luis Menchén11Fiona M. Gribble12Frank Reimann13Luis G. Guijarro14Jose M. Carrascosa15Ángela M. Valverde16Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain; Centro de Biología Molecular Severo Ochoa (CBMSO, CSIC-UAM), Madrid, SpainInstituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; CIBER de Enfermedades Hepáticas y Digestivas (CIBERHED), ISCIII, Madrid, SpainDepartamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense, Madrid, SpainWellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UKInstituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, SpainDepartamento de Biología de Sistemas, Universidad de Alcalá de Henares, Madrid, SpainDepartamento de Biología de Sistemas, Universidad de Alcalá de Henares, Madrid, SpainCEMBIO, Universidad San Pablo-CEU, Madrid, SpainCEMBIO, Universidad San Pablo-CEU, Madrid, SpainCEMBIO, Universidad San Pablo-CEU, Madrid, SpainInstituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; CIBER de Enfermedades Hepáticas y Digestivas (CIBERHED), ISCIII, Madrid, Spain; Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, SpainWellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UKWellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UKDepartamento de Biología de Sistemas, Universidad de Alcalá de Henares, Madrid, SpainCentro de Biología Molecular Severo Ochoa (CBMSO, CSIC-UAM), Madrid, Spain; Corresponding author. Centro de Biología Molecular Severo Ochoa (CBMSO, CSIC-UAM), Madrid, Spain.Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain; Corresponding author. Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain. Fax: +34-91-5854401.Objective: Non-alcoholic steatohepatitis (NASH) is characterized by a robust pro-inflammatory component at both hepatic and systemic levels together with a disease-specific gut microbiome signature. Protein tyrosine phosphatase 1 B (PTP1B) plays distinct roles in non-immune and immune cells, in the latter inhibiting pro-inflammatory signaling cascades. In this study, we have explored the role of PTP1B in the composition of gut microbiota and gut barrier dynamics in methionine and choline-deficient (MCD) diet-induced NASH in mice. Methods: Gut features and barrier permeability were characterized in wild-type (PTP1B WT) and PTP1B-deficient knockout (PTP1B KO) mice fed a chow or methionine/choline-deficient (MCD) diet for 4 weeks. The impact of inflammation was studied in intestinal epithelial and enteroendocrine cells. The secretion of GLP-1 was evaluated in primary colonic cultures and plasma of mice. Results: We found that a shift in the gut microbiota shape, disruption of gut barrier function, higher levels of serum bile acids, and decreased circulating glucagon-like peptide (GLP)-1 are features during NASH. Surprisingly, despite the pro-inflammatory phenotype of global PTP1B-deficient mice, they were partly protected against the alterations in gut microbiota composition during NASH and presented better gut barrier integrity and less permeability under this pathological condition. These effects concurred with higher colonic mucosal inflammation, decreased serum bile acids, and protection against the decrease in circulating GLP-1 levels during NASH compared with their WT counterparts together with increased expression of GLP-2-sensitive genes in the gut. At the molecular level, stimulation of enteroendocrine STC-1 cells with a pro-inflammatory conditioned medium (CM) from lipopolysaccharide (LPS)-stimulated macrophages triggered pro-inflammatory signaling cascades that were further exacerbated by a PTP1B inhibitor. Likewise, the pro-inflammatory CM induced GLP-1 secretion in primary colonic cultures, an effect augmented by PTP1B inhibition. Conclusion: Altogether our results have unraveled a potential role of PTP1B in the gut–liver axis during NASH, likely mediated by increased sensitivity to GLPs, with potential therapeutic value. Keywords: NASH, PTP1B, Inflammation, Gut microbiota, GLP-1, GLP-2http://www.sciencedirect.com/science/article/pii/S2212877820300260 |
| spellingShingle | Carmen Rubio Marta Puerto Juan J. García-Rodríquez Van B. Lu Irma García-Martínez Rosa Alén Patricia Sanmartín-Salinas M. Val Toledo-Lobo Jorge Saiz Javier Ruperez Coral Barbas Luis Menchén Fiona M. Gribble Frank Reimann Luis G. Guijarro Jose M. Carrascosa Ángela M. Valverde Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice Molecular Metabolism |
| title | Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice |
| title_full | Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice |
| title_fullStr | Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice |
| title_full_unstemmed | Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice |
| title_short | Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice |
| title_sort | impact of global ptp1b deficiency on the gut barrier permeability during nash in mice |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820300260 |
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