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2021-2028"]}],"id":[{"id":"10.13039\/501100003768","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["egastro"],"accepted":{"date-parts":[[2025,1,8]]},"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Impaired hepatic expression of protein tyrosine phosphatase delta (\n                      <jats:italic>PTPRD<\/jats:italic>\n                      ) is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection. However, the\n                      <jats:italic>PTPRD<\/jats:italic>\n                      -expressing hepatic cell types, signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We studied\n                      <jats:italic>PTPRD<\/jats:italic>\n                      expression in single-cell and bulk liver transcriptomic data from mice and humans, and established a\n                      <jats:italic>Ptprd<\/jats:italic>\n                      -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\n                      <jats:italic>PTPRD<\/jats:italic>\n                      expression and analysing its association with metabolic disease markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The analysis of individuals ranked according to\n                      <jats:italic>PTPRD<\/jats:italic>\n                      expression and\n                      <jats:italic>Ptprd<\/jats:italic>\n                      -deficient mice, showed that\n                      <jats:italic>PTPRD<\/jats:italic>\n                      levels were associated with hepatic glucose\/lipid signalling and peroxisome function. Hepatic\n                      <jats:italic>PTPRD<\/jats:italic>\n                      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\n                      <jats:italic>Ptprd<\/jats:italic>\n                      +\/\u2212 mice\u2009and a pronounced unfolded protein response, which impacts insulin signalling. Accordingly, silencing of\n                      <jats:italic>PTPRD<\/jats:italic>\n                      blunted insulin-induced AKT phosphorylation. Patients with obesity and low hepatic\n                      <jats:italic>PTPRD<\/jats:italic>\n                      expression exhibit increased levels of metabolic risk factors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/egastro-2024-100159","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T12:15:43Z","timestamp":1737980143000},"page":"e100159","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease"],"prefix":"10.1136","volume":"3","author":[{"given":"Armando Andres","family":"Roca Suarez","sequence":"first","affiliation":[{"name":"Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"},{"name":"Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France"},{"name":"University of Lyon, Universit\u00e9 Claude-Bernard (UCBL), Lyon, France"},{"name":"The Lyon Hepatology Institute, IHU EVEREST, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"J\u00fchling","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Moehlin","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Mailly","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"},{"name":"\u00c6PIC Animal Facility Platform, Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Virz\u00ec","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Brignon","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"},{"name":"\u00c6PIC Animal Facility Platform, Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah C","family":"Durand","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine A","family":"Oudot","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenie","family":"Schaeffer","sequence":"additional","affiliation":[{"name":"Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, 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