TY - GEN
T1 - Protein tyrosine phosphatase receptor kappa regulates glycolysis andde novolipogenesis to promote hepatocyte metabolic reprogramming in obesity
AU - Gilglioni, EH
AU - Li, A
AU - St-Pierre-Wijckmans, W
AU - Shen, T
AU - Pérez-Chávez, I
AU - Hovhannisyan, G
AU - Lisjak, M
AU - Negueruela, J
AU - Vandenbempt, V
AU - Bauzá-Martinez, J
AU - Herranz, JM
AU - Ezeriņa, Daria
AU - Demine, Stéphane
AU - Feng, Z
AU - Vignane, T
AU - Otero-Sánchez, L
AU - Lambertucci, F
AU - Prašnická , A
AU - Devière, J
AU - Hay, DC
AU - Encinar, José Antonio
AU - Singh, SP
AU - Messens, Joris
AU - Filipovic, MR
AU - Sharpe, HJ
AU - Trépo, Eric
AU - Wu, W.
AU - Gurzov, EN
N1 - bioRxiv 2023.12.01.569004; doi: https://doi.org/10.1101/2023.12.01.569004
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://europepmc.org/abstract/PPR/PPR767325
U2 - 10.1101/2023.12.01.569004
DO - 10.1101/2023.12.01.569004
M3 - Other contribution
ER -