Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease
Objective Impaired hepatic expression of protein tyrosine phosphatase delta (PTPRD) is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection. However, the PTPRD-expressing hepatic cell types, s...
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2025-01-01
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| Series: | eGastroenterology |
| Online Access: | https://egastroenterology.bmj.com/content/3/1/e100159.full |
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| author | Thomas F Baumert Charlotte Bach Patrick Pessaux Catherine Schuster Frank Jühling Sarah C Durand Yujin Hoshida Fabien Zoulim Atish Mukherji Naoto Fujiwara Marine A Oudot Armando Andres Roca Suarez Michel L Tremblay Barbara Testoni Joachim Lupberger Romain Parent Laurent Mailly Nassim Dali-Youcef Emanuele Felli Maria Saez-Palma Julien Moehlin Alessia Virzì Nicolas Brignon Eugenie Schaeffer Romain Martin Laura Meiss-Heydmann Zakaria Boulahtouf Lea Girard Emma Osswald Carole Jamey Daniel Brumaru Bhuvaneswari Koneru |
| author_facet | Thomas F Baumert Charlotte Bach Patrick Pessaux Catherine Schuster Frank Jühling Sarah C Durand Yujin Hoshida Fabien Zoulim Atish Mukherji Naoto Fujiwara Marine A Oudot Armando Andres Roca Suarez Michel L Tremblay Barbara Testoni Joachim Lupberger Romain Parent Laurent Mailly Nassim Dali-Youcef Emanuele Felli Maria Saez-Palma Julien Moehlin Alessia Virzì Nicolas Brignon Eugenie Schaeffer Romain Martin Laura Meiss-Heydmann Zakaria Boulahtouf Lea Girard Emma Osswald Carole Jamey Daniel Brumaru Bhuvaneswari Koneru |
| author_sort | Thomas F Baumert |
| collection | DOAJ |
| description | Objective Impaired hepatic expression of protein tyrosine phosphatase delta (PTPRD) is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection. However, the PTPRD-expressing hepatic cell types, signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans, and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis (MASH). Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays. The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice, showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function. Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease. We further validated PTPRD as a STAT3 phosphatase in the liver, acting as a regulator of peroxisomal fatty acid metabolism. During MASH, low PTPRD led to increased liver steatosis in Ptprd+/− mice and a pronounced unfolded protein response, which impacts insulin signalling. Accordingly, silencing of PTPRD blunted insulin-induced AKT phosphorylation. Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis, which is recapitulated in clinical manifestations of metabolic liver disease. |
| format | Article |
| id | doaj-art-9629e60656de4445bbeeeb7f821d2aa0 |
| institution | Kabale University |
| issn | 2766-0125 2976-7296 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
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| series | eGastroenterology |
| spelling | doaj-art-9629e60656de4445bbeeeb7f821d2aa02025-02-12T09:20:10ZengBMJ Publishing GroupeGastroenterology2766-01252976-72962025-01-013110.1136/egastro-2024-100159Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver diseaseThomas F Baumert0Charlotte Bach1Patrick Pessaux2Catherine Schuster3Frank Jühling4Sarah C Durand5Yujin Hoshida6Fabien Zoulim7Atish Mukherji8Naoto Fujiwara9Marine A Oudot10Armando Andres Roca Suarez11Michel L Tremblay12Barbara Testoni13Joachim Lupberger14Romain Parent15Laurent Mailly16Nassim Dali-Youcef17Emanuele Felli18Maria Saez-Palma19Julien Moehlin20Alessia Virzì21Nicolas Brignon22Eugenie Schaeffer23Romain Martin24Laura Meiss-Heydmann25Zakaria Boulahtouf26Lea Girard27Emma Osswald28Carole Jamey29Daniel Brumaru30Bhuvaneswari Koneru3116 Institut Universitaire de France (IUF), Paris, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France11 Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA2 Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France11 Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France13 Rosalind and Morris Goodman Cancer Institute, Montreal, Quebec, Canada2 Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France2 Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France6 Laboratoire de Biochimie et de Biologie Moléculaire, Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France2 Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France1 Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France6 Laboratoire de Biochimie et de Biologie Moléculaire, Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France6 Laboratoire de Biochimie et de Biologie Moléculaire, Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France11 Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USAObjective Impaired hepatic expression of protein tyrosine phosphatase delta (PTPRD) is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection. However, the PTPRD-expressing hepatic cell types, signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans, and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis (MASH). Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays. The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice, showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function. Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease. We further validated PTPRD as a STAT3 phosphatase in the liver, acting as a regulator of peroxisomal fatty acid metabolism. During MASH, low PTPRD led to increased liver steatosis in Ptprd+/− mice and a pronounced unfolded protein response, which impacts insulin signalling. Accordingly, silencing of PTPRD blunted insulin-induced AKT phosphorylation. Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis, which is recapitulated in clinical manifestations of metabolic liver disease.https://egastroenterology.bmj.com/content/3/1/e100159.full |
| spellingShingle | Thomas F Baumert Charlotte Bach Patrick Pessaux Catherine Schuster Frank Jühling Sarah C Durand Yujin Hoshida Fabien Zoulim Atish Mukherji Naoto Fujiwara Marine A Oudot Armando Andres Roca Suarez Michel L Tremblay Barbara Testoni Joachim Lupberger Romain Parent Laurent Mailly Nassim Dali-Youcef Emanuele Felli Maria Saez-Palma Julien Moehlin Alessia Virzì Nicolas Brignon Eugenie Schaeffer Romain Martin Laura Meiss-Heydmann Zakaria Boulahtouf Lea Girard Emma Osswald Carole Jamey Daniel Brumaru Bhuvaneswari Koneru Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease eGastroenterology |
| title | Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease |
| title_full | Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease |
| title_fullStr | Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease |
| title_full_unstemmed | Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease |
| title_short | Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease |
| title_sort | protein tyrosine phosphatase delta is a stat3 phosphatase and suppressor of metabolic liver disease |
| url | https://egastroenterology.bmj.com/content/3/1/e100159.full |
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