PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity
Year: 2024
Type: article
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. PTPRK is a key protein in the transformation of normal to tumorigenic liver cells in obesity, providing fuel and lipids. Here, the authors show that genetic deletion of PTPRK in mice protects against fatty liver in an obesogenic diet and the development of liver cancer.
Source: Nature Communications
Authors: 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
Institutions: Université Libre de Bruxelles, Vrije Universiteit Brussel, Vlaams Instituut voor Biotechnologie, VIB-VUB Center for Structural Biology, Utrecht University, Netherlands Proteomics Centre, Centro de Investigación Médica Aplicada, Universidad de Navarra, Leibniz Institute for Analytical Sciences - ISAS, MRC Centre for Regenerative Medicine, University of Edinburgh, Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Babraham Institute, Agency for Science, Technology and Research, National University of Singapore, Singapore Immunology Network, Walloon Excellence in Lifesciences and Biotechnology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G2460981159, G4694513774, G9000324276
OpenAlex ID: W4404020283