PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity
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.
Authors
- Alena Prašnická (ORCID: https://orcid.org/0000-0002-6671-0318)
- Tzu-Keng Shen
- Flavia Lambertucci (ORCID: https://orcid.org/0000-0002-2719-6635)
- Wei Wu (ORCID: https://orcid.org/0000-0002-1092-603X)
- Eduardo Hideo Gilglioni (ORCID: https://orcid.org/0000-0001-5137-4051)
- Stéphane Demine (ORCID: https://orcid.org/0000-0002-7254-2269)
- Julia Bauzá‐Martinez (ORCID: https://orcid.org/0000-0002-5865-5830)
- David C. Hay (ORCID: https://orcid.org/0000-0002-7593-5973)
- Miloš R. Filipović (ORCID: https://orcid.org/0000-0003-0060-0041)
- Michela Lisjak
- Daria Ezeriņa (ORCID: https://orcid.org/0000-0002-3104-7093)
- Eric Trépo (ORCID: https://orcid.org/0000-0003-0475-3934)
- Esteban N. Gurzov (ORCID: https://orcid.org/0000-0003-4642-0273)
- Lukas Otero Sanchez (ORCID: https://orcid.org/0000-0002-8013-1371)
- Hayley J. Sharpe (ORCID: https://orcid.org/0000-0002-4723-298X)
- José M. Herranz (ORCID: https://orcid.org/0000-0002-6031-535X)
- Thibaut Vignane (ORCID: https://orcid.org/0000-0002-3377-3187)
- Valerie Vandenbempt (ORCID: https://orcid.org/0000-0003-3104-8499)
- Joris Messens (ORCID: https://orcid.org/0000-0002-2128-8264)
- Javier Negueruela (ORCID: https://orcid.org/0000-0001-7967-5067)
- José Antonio Encinar (ORCID: https://orcid.org/0000-0002-7219-3863)
- Sumeet Pal Singh (ORCID: https://orcid.org/0000-0002-5154-3318)
- Israel Pérez-Chávez (ORCID: https://orcid.org/0000-0002-3270-194X)
- Wadsen St‐Pierre‐Wijckmans (ORCID: https://orcid.org/0009-0005-1080-6117)
- Ao Li (ORCID: https://orcid.org/0000-0001-7861-6313)
- Feng Zheng (ORCID: https://orcid.org/0000-0002-1829-6183)
- Jacques Devière (ORCID: https://orcid.org/0000-0003-1889-1924)
- Garnik Hovhannisyan
Institutions
- Agency for Science, Technology and Research (SG)
- Babraham Institute (GB)
- Université Libre de Bruxelles (BE)
- Vrije Universiteit Brussel (BE)
- National University of Singapore (SG)
- Utrecht University (NL)
- Singapore Immunology Network (SG)
- Vlaams Instituut voor Biotechnologie (BE)
- Netherlands Metabolomics Centre (NL)
- MRC Centre for Regenerative Medicine (GB)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- VIB-VUB Center for Structural Biology (BE)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- Universidad de Navarra (ES)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-04
- DOI
- https://doi.org/10.1038/s41467-024-53733-0
- Citations
- 16
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 5.22
Funders
- Biotechnology and Biological Sciences Research Council