2. Academic Validation
  3. PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity

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

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. esteban.gurzov@ulb.be.
  • 18 WELBIO Department, WEL Research Institute, B-1300, Wavre, Belgium. esteban.gurzov@ulb.be.
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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