PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity
Abstract Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs)...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53733-0 |
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| author | Eduardo H. Gilglioni Ao Li Wadsen St-Pierre-Wijckmans Tzu-Keng Shen Israel Pérez-Chávez Garnik Hovhannisyan Michela Lisjak Javier Negueruela Valerie Vandenbempt Julia Bauzá-Martinez Jose M. Herranz Daria Ezeriņa Stéphane Demine Zheng Feng Thibaut Vignane Lukas Otero Sanchez Flavia Lambertucci Alena Prašnická Jacques Devière David C. Hay Jose A. Encinar Sumeet Pal Singh Joris Messens Milos R. Filipovic Hayley J. Sharpe Eric Trépo Wei Wu Esteban N. Gurzov |
| author_facet | Eduardo H. Gilglioni Ao Li Wadsen St-Pierre-Wijckmans Tzu-Keng Shen Israel Pérez-Chávez Garnik Hovhannisyan Michela Lisjak Javier Negueruela Valerie Vandenbempt Julia Bauzá-Martinez Jose M. Herranz Daria Ezeriņa Stéphane Demine Zheng Feng Thibaut Vignane Lukas Otero Sanchez Flavia Lambertucci Alena Prašnická Jacques Devière David C. Hay Jose A. Encinar Sumeet Pal Singh Joris Messens Milos R. Filipovic Hayley J. Sharpe Eric Trépo Wei Wu Esteban N. Gurzov |
| author_sort | Eduardo H. Gilglioni |
| collection | DOAJ |
| description | Abstract Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity. |
| format | Article |
| id | doaj-art-47d15d12bd9c4154ade149ceeddbddb9 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-47d15d12bd9c4154ade149ceeddbddb92024-11-10T12:31:40ZengNature PortfolioNature Communications2041-17232024-11-0115112210.1038/s41467-024-53733-0PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesityEduardo H. Gilglioni0Ao Li1Wadsen St-Pierre-Wijckmans2Tzu-Keng Shen3Israel Pérez-Chávez4Garnik Hovhannisyan5Michela Lisjak6Javier Negueruela7Valerie Vandenbempt8Julia Bauzá-Martinez9Jose M. Herranz10Daria Ezeriņa11Stéphane Demine12Zheng Feng13Thibaut Vignane14Lukas Otero Sanchez15Flavia Lambertucci16Alena Prašnická17Jacques Devière18David C. Hay19Jose A. Encinar20Sumeet Pal Singh21Joris Messens22Milos R. Filipovic23Hayley J. Sharpe24Eric Trépo25Wei Wu26Esteban N. Gurzov27Signal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesBiomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht UniversityHepatology Program, CIMA, University of NavarraVIB-VUB Center for Structural Biology, Vlaams Instituut voor BiotechnologieSignal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesLeibniz Institute for Analytical Sciences, ISAS e.V.Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesSignal Transduction and Metabolism Laboratory, Université libre de BruxellesDepartment of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de BruxellesCentre for Regenerative Medicine, Institute for Regeneration and Repair, The University of EdinburghInstituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDIBE)IRIBHM, Université libre de BruxellesVIB-VUB Center for Structural Biology, Vlaams Instituut voor BiotechnologieLeibniz Institute for Analytical Sciences, ISAS e.V.Signalling Programme, Babraham InstituteDepartment of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de BruxellesBiomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht UniversitySignal Transduction and Metabolism Laboratory, Université libre de BruxellesAbstract Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity.https://doi.org/10.1038/s41467-024-53733-0 |
| spellingShingle | Eduardo H. Gilglioni Ao Li Wadsen St-Pierre-Wijckmans Tzu-Keng Shen Israel Pérez-Chávez Garnik Hovhannisyan Michela Lisjak Javier Negueruela Valerie Vandenbempt Julia Bauzá-Martinez Jose M. Herranz Daria Ezeriņa Stéphane Demine Zheng Feng Thibaut Vignane Lukas Otero Sanchez Flavia Lambertucci Alena Prašnická Jacques Devière David C. Hay Jose A. Encinar Sumeet Pal Singh Joris Messens Milos R. Filipovic Hayley J. Sharpe Eric Trépo Wei Wu Esteban N. Gurzov PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity Nature Communications |
| title | PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity |
| title_full | PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity |
| title_fullStr | PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity |
| title_full_unstemmed | PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity |
| title_short | PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity |
| title_sort | ptprk regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity |
| url | https://doi.org/10.1038/s41467-024-53733-0 |
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