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

  • Nat Commun. 2024 Nov 4;15(1):9522. doi: 10.1038/s41467-024-53733-0.
Eduardo H Gilglioni  1 ,  Ao Li  1 ,  Wadsen St-Pierre-Wijckmans  1 ,  Tzu-Keng Shen  1  2  3  4 ,  Israel Pérez-Chávez  1  2  3  4 ,  Garnik Hovhannisyan  1 ,  Michela Lisjak  1 ,  Javier Negueruela  1 ,  Valerie Vandenbempt  1 ,  Julia Bauzá-Martinez  5  6 ,  Jose M Herranz  7 ,  Daria Ezeriņa  2  3  4 ,  Stéphane Demine  1 ,  Zheng Feng  1 ,  Thibaut Vignane  8 ,  Lukas Otero Sanchez  9  10 ,  Flavia Lambertucci  1 ,  Alena Prašnická  1 ,  Jacques Devière  9  10 ,  David C Hay  11 ,  Jose A Encinar  12 ,  Sumeet Pal Singh  13 ,  Joris Messens  2  3  4 ,  Milos R Filipovic  8 ,  Hayley J Sharpe  14 ,  Eric Trépo  9  10 ,  Wei Wu  5  6  15  16 ,  Esteban N Gurzov  17  18
Affiliations
  • 1. Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium.
  • 2. VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium.
  • 3. Structural Biology Brussels, Vrije Universiteit Brussel, B-1050, Brussels, Belgium.
  • 4. Brussels Center for Redox Biology, Vrije Universiteit Brussel, B-1050, Brussels, Belgium.
  • 5. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH, Utrecht, The Netherlands.
  • 6. Netherlands Proteomics Centre, 3584 CH, Utrecht, The Netherlands.
  • 7. Hepatology Program, CIMA, University of Navarra, 31009, Pamplona, Spain.
  • 8. Leibniz Institute for Analytical Sciences, ISAS e.V., 44139, Dortmund, Germany.
  • 9. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, B-1070, Brussels, Belgium.
  • 10. Laboratory of Experimental Gastroenterology, Université libre de Bruxelles, B-1070, Brussels, Belgium.
  • 11. Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, EH16 4UU, UK.
  • 12. Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDIBE), 03202, Elche, Spain.
  • 13. IRIBHM, Université libre de Bruxelles, B-1070, Brussels, Belgium.
  • 14. Signalling Programme, Babraham Institute, Cambridge, CB22 3AT, UK.
  • 15. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore.
  • 16. Department of Pharmacy & Pharmaceutical Sciences, National University of Singapore, Singapore, 117543, Singapore.
  • 17. Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium. [email protected].
  • 18. WELBIO Department, WEL Research Institute, B-1300, Wavre, Belgium. [email protected].
PMID: 39496584 DOI: 10.1038/s41467-024-53733-0
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.

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