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

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 and Esteban N. Gurzov ()
Additional contact information
Eduardo H. Gilglioni: Université libre de Bruxelles
Ao Li: Université libre de Bruxelles
Wadsen St-Pierre-Wijckmans: Université libre de Bruxelles
Tzu-Keng Shen: Université libre de Bruxelles
Israel Pérez-Chávez: Université libre de Bruxelles
Garnik Hovhannisyan: Université libre de Bruxelles
Michela Lisjak: Université libre de Bruxelles
Javier Negueruela: Université libre de Bruxelles
Valerie Vandenbempt: Université libre de Bruxelles
Julia Bauzá-Martinez: Utrecht University
Jose M. Herranz: University of Navarra
Daria Ezeriņa: Vlaams Instituut voor Biotechnologie
Stéphane Demine: Université libre de Bruxelles
Zheng Feng: Université libre de Bruxelles
Thibaut Vignane: ISAS e.V.
Lukas Otero Sanchez: Hôpital Universitaire de Bruxelles
Flavia Lambertucci: Université libre de Bruxelles
Alena Prašnická: Université libre de Bruxelles
Jacques Devière: Hôpital Universitaire de Bruxelles
David C. Hay: The University of Edinburgh
Jose A. Encinar: Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDIBE)
Sumeet Pal Singh: Université libre de Bruxelles
Joris Messens: Vlaams Instituut voor Biotechnologie
Milos R. Filipovic: ISAS e.V.
Hayley J. Sharpe: Babraham Institute
Eric Trépo: Hôpital Universitaire de Bruxelles
Wei Wu: Utrecht University
Esteban N. Gurzov: Université libre de Bruxelles

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53733-0

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