Protein tyrosine phosphatase receptor kappa regulates glycolysis and<i>de novo</i>lipogenesis to promote hepatocyte metabolic reprogramming in obesity

EH Gilglioni, A Li, W St-Pierre-Wijckmans, T Shen, I Pérez-Chávez, G Hovhannisyan, M Lisjak, J Negueruela, V Vandenbempt, J Bauzá-Martinez, JM Herranz, Daria Ezeriņa, Stéphane Demine, Z Feng, T Vignane, L Otero-Sánchez, F Lambertucci, A Prašnická , J Devière, DC HayJosé Antonio Encinar, SP Singh, Joris Messens, MR Filipovic, HJ Sharpe, Eric Trépo, W. Wu, EN Gurzov

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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 positively correlated with PPARγ-induced lipogenic signalling. High-fat-fed PTPRK knockout mice displayed reduced weight gain and 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. Silencing PTPRK in hepatoma cell lines resulted in reduced colony-forming ability and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis. Our study defines a novel role for PTPRK in regulating hepatic glycolysis, lipid metabolism, and tumour development. PTPRK inhibition may provide therapeutic possibilities in obesity-associated liver diseases.
Original languageUndefined/Unknown
DOIs
Publication statusPublished - Dec 2023

Bibliographical note

bioRxiv 2023.12.01.569004; doi: https://doi.org/10.1101/2023.12.01.569004

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