TY - JOUR
T1 - PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity
AU - Gilglioni, Eduardo H
AU - Li, Ao
AU - St-Pierre-Wijckmans, Wadsen
AU - Shen, Tzu-Keng
AU - Pérez-Chávez, Israel
AU - Hovhannisyan, Garnik
AU - Lisjak, Michela
AU - Negueruela, Javier
AU - Vandenbempt, Valerie
AU - Bauzá-Martinez, Julia
AU - Herranz, Jose M
AU - Ezeriņa, Daria
AU - Demine, Stéphane
AU - Feng, Zheng
AU - Vignane, Thibaut
AU - Otero Sanchez, Lukas
AU - Lambertucci, Flavia
AU - Prašnická, Alena
AU - Devière, Jacques
AU - Hay, David C
AU - Encinar, Jose A
AU - Singh, Sumeet Pal
AU - Messens, Joris
AU - Filipovic, Milos R
AU - Sharpe, Hayley J
AU - Trépo, Eric
AU - Wu, Wei
AU - Gurzov, Esteban N
N1 - © 2024. The Author(s).
PY - 2024/11/4
Y1 - 2024/11/4
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 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.
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 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.
KW - Animals
KW - Lipogenesis/genetics
KW - Glycolysis
KW - Hepatocytes/metabolism
KW - Obesity/metabolism
KW - Humans
KW - Mice, Knockout
KW - Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism
KW - Male
KW - Mice
KW - Female
KW - Liver/metabolism
KW - PPAR gamma/metabolism
KW - Liver Neoplasms/metabolism
KW - Mice, Inbred C57BL
KW - Diet, High-Fat/adverse effects
KW - Fatty Liver/metabolism
KW - Lipid Metabolism
KW - Metabolic Reprogramming
UR - http://www.scopus.com/inward/record.url?scp=85208517288&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-53733-0
DO - 10.1038/s41467-024-53733-0
M3 - Article
C2 - 39496584
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 9522
ER -