PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.

Autor: Gilglioni EH; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Li A; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., St-Pierre-Wijckmans W; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Shen TK; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium.; VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium.; Structural Biology Brussels, Vrije Universiteit Brussel, B-1050, Brussels, Belgium.; Brussels Center for Redox Biology, Vrije Universiteit Brussel, B-1050, Brussels, Belgium., Pérez-Chávez I; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium.; VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium.; Structural Biology Brussels, Vrije Universiteit Brussel, B-1050, Brussels, Belgium.; Brussels Center for Redox Biology, Vrije Universiteit Brussel, B-1050, Brussels, Belgium., Hovhannisyan G; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Lisjak M; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Negueruela J; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Vandenbempt V; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Bauzá-Martinez J; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH, Utrecht, The Netherlands.; Netherlands Proteomics Centre, 3584 CH, Utrecht, The Netherlands., Herranz JM; Hepatology Program, CIMA, University of Navarra, 31009, Pamplona, Spain., Ezeriņa D; VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium.; Structural Biology Brussels, Vrije Universiteit Brussel, B-1050, Brussels, Belgium.; Brussels Center for Redox Biology, Vrije Universiteit Brussel, B-1050, Brussels, Belgium., Demine S; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Feng Z; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Vignane T; Leibniz Institute for Analytical Sciences, ISAS e.V., 44139, Dortmund, Germany., Otero Sanchez L; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, B-1070, Brussels, Belgium.; Laboratory of Experimental Gastroenterology, Université libre de Bruxelles, B-1070, Brussels, Belgium., Lambertucci F; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Prašnická A; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium., Devière J; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, B-1070, Brussels, Belgium.; Laboratory of Experimental Gastroenterology, Université libre de Bruxelles, B-1070, Brussels, Belgium., Hay DC; Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, EH16 4UU, UK., Encinar JA; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDIBE), 03202, Elche, Spain., Singh SP; IRIBHM, Université libre de Bruxelles, B-1070, Brussels, Belgium., Messens J; VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium.; Structural Biology Brussels, Vrije Universiteit Brussel, B-1050, Brussels, Belgium.; Brussels Center for Redox Biology, Vrije Universiteit Brussel, B-1050, Brussels, Belgium., Filipovic MR; Leibniz Institute for Analytical Sciences, ISAS e.V., 44139, Dortmund, Germany., Sharpe HJ; Signalling Programme, Babraham Institute, Cambridge, CB22 3AT, UK., Trépo E; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, B-1070, Brussels, Belgium.; Laboratory of Experimental Gastroenterology, Université libre de Bruxelles, B-1070, Brussels, Belgium., Wu W; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH, Utrecht, The Netherlands.; Netherlands Proteomics Centre, 3584 CH, Utrecht, The Netherlands.; Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore.; Department of Pharmacy & Pharmaceutical Sciences, National University of Singapore, Singapore, 117543, Singapore., Gurzov EN; Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium. esteban.gurzov@ulb.be.; WELBIO Department, WEL Research Institute, B-1300, Wavre, Belgium. esteban.gurzov@ulb.be.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 04; Vol. 15 (1), pp. 9522. Date of Electronic Publication: 2024 Nov 04.
DOI: 10.1038/s41467-024-53733-0
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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