Mechanistic Insights into PTPRK-mediated Hepatic Metabolic Regulation — ASN Events
  1. Schedule
  2. Lunch & Poster Session 2
  3. Mechanistic Insights into PTPRK-mediated Hepatic Metabolic Regulation

Mechanistic Insights into PTPRK-mediated Hepatic Metabolic Regulation (#107)

Amanda Crystal Wei Jin Lee 1 , Eduardo Hideo Gilglioni 2 , Justin Jun Ting Low 1 , Esteban N. Gurov 2 3 , Wei Wu 1 4 5
  1. Singapore Immunology Network, SIgN, A*STAR, Singapore, SINGAPORE
  2. Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles (ULB), Brussels, Belgium
  3. WELBIO Department, WEL Research Institute, Wavre, Belgium
  4. Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht Univeristy, Utrecht, The Netherlands
  5. Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore

Phosphorylation-dependent signaling is maintained by opposing functions of kinase and phosphatases. In metabolic diseases, this phosphorylation-dephosphorylation balance is often dysregulated, wherein protein tyrosine phosphatases (PTPs) have been linked to obesity1, and is a major risk factor for associated liver dysfunction2. In particular, Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) is involved in metabolic reprogramming and progression of metabolic dysfunction-associated steatotic liver disease (MASLD)3. To further elucidate its role, we profiled the Ptprk-/- mice responses to normal chow diet and high-fat, high-fructose, and high-cholesterol (HFHFHC) diet, using quantitative phosphoproteomics as a readout. To our surprise, although PTPRK is primarily expressed in the liver, we observed little changes on liver tyrosine phosphorylations. This challenges the phosphatase function of PTPRK, to instead suggest a broadly regulatory role of PTPRK as a metabolic switch, as PTPRK knockout mice remained lean despite being on a HFHFHC diet. Deeper analyses supporting the lean phenotype revealed significantly downregulated phosphosites associated with lipid biosynthesis, alongside the suppression of TOR and TORC1 signaling pathways – both of which are usually overactivated in MASLD. This further unfolds the critical regulatory role of PTPRK beyond dephosphorylation, and its prospect as a therapeutic target for liver diseases such as MASLD and metabolic dysfunction-associated steatohepatits (MASH).

  1. Brenachot, X. et al. Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance. Nature Communications 8, 1820, doi:10.1038/s41467-017-02074-2 (2017).
  2. Simancas-Racines, D. et al. Nutritional Strategies for Battling Obesity-Linked Liver Disease: the Role of Medical Nutritional Therapy in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Management. Current Obesity Reports 14, 7, doi:10.1007/s13679-024-00597-6 (2025).
  3. Gilglioni, E. H. et al. PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity. Nature Communications 15, 9522, doi:10.1038/s41467-024-53733-0 (2024).