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 HayJose A Encinar, Sumeet Pal Singh, Joris Messens, Milos R Filipovic, Hayley J Sharpe, Eric Trépo, Wei Wu, Esteban N Gurzov

Onderzoeksoutput: Articlepeer review

Samenvatting

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.

Originele taal-2English
Artikelnummer9522
Aantal pagina's22
TijdschriftNature communications
Volume15
Nummer van het tijdschrift1
DOI's
StatusPublished - 4 nov 2024

Bibliografische nota

© 2024. The Author(s).

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