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PTPRF regulates actin cytoskeleton dynamics to reduce mitochondrial activity and insulin sensitivity in obesity-associated liver dysfunction

par Saint-pierre Wijckmans, Wadsen
Président du jury Dewachter, Laurence
Promoteur Gurzov, Esteban Nicolas
Publication Non publié, 2026-01-20

Thèse de doctorat

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Résumé :

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disorder. While insulin resistance and inflammatory pathways are well- established drivers of MALSD, the role of hepatic cytoskeletal remodeling has remained unclear. Human liver proteomics across MASLD stages revealed progressive cytoskeletal remodeling and a striking pattern of receptor-type protein tyrosine phosphatase F (PTPRF) downregulation from healthy liver through steatosis to MASH, with re-expression in hepatocellular carcinoma. This downregulation is mechanistically driven by saturated free fatty acid induced XBP1s signaling. Hepatocyte-specific PTPRF deletion in mice conferred metabolic protection, enhancing insulin receptor and AKT phosphorylation as well as improving mitochondrial respiratory capacity under dietary stress. Conversely, PTPRF overexpression impaired insulin sensitivity and shifted hepatocytes toward glycolytic metabolism. Substrate-trapping interactomics identified actin regulatory proteins as key targets of PTPRF. We demonstrated that perturbation of actin polymerization impaired lipid-droplet accumulation in hepatocytes, revealing how cytoskeletal dynamics directly influence steatosis. Consistent with this observation, PTPRF deficiency reduced fat accumulation in hepatocytes and steatosis development in obese mice. Moreover, PTPRF deficiency reduced hepatocellular carcinoma proliferation in human cell lines but did not impact on a carcinogen and diet-induced hepatocellular carcinoma mouse model. Taken together, we identified PTPRF as a central regulator of hepatocyte structure-function coupling that integrates cytoskeleton architecture with elevated oxidative capacity, reduced steatosis, and enhanced insulin sensitivity. We propose PTPRF as a novel target to improve the early stages of liver dysfunction in obesity, without risk of liver cancer development.