title: Protein Tyrosine Phosphatase 1B (PTP1B) deficiency accelerates hepatic regeneration in mice.
abstract: Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of metabolism and cell growth by its ability to dephosphorylate tyrosine kinase receptors and modulate the intensity of their signaling cascades. Because liver regeneration involves tyrosine phosphorylation-mediated signaling, we investigated the role of PTP1B in this process by performing partial hepatectomy in wild-type (PTP1B(+/+)) and PTP1B-deficient (PTP1B(-/-)) mice. The expression of PCNA and cyclins D1 and E (cell proliferation markers) was enhanced in PTP1B(-/-) regenerating livers, in parallel with 5'-bromo-2'-deoxyuridine incorporation. Phosphorylation of JNK1/2 and STAT3, early triggers of hepatic regeneration in response to TNF-α and IL-6, was accelerated in PTP1B(-/-) mice compared with PTP1B(+/+) mice. These phosphorylations were increased in PTP1B(-/-) hepatocytes or by silencing PTP1B in wild-type cells and decreased further after the addition of recombinant PTP1B. Enhanced EGF- and HGF receptor-mediated signaling was observed in regenerating livers lacking PTP1B and in EGF- or HGF-stimulated PTP1B(-/-) hepatocytes. Moreover, PTP1B(-/-) mice displayed a more rapid increase in intrahepatic lipid accumulation than PTP1B(+/+) control mice. Late responses to partial hepatectomy revealed additional divergences because stress-mediated signaling was attenuated at 24 to 96 hours in PTP1B(-/-) mice compared with PTP1B(+/+) mice. Finally, PTP1B deficiency also improves hepatic regeneration in mice fed a high-fat diet. These results suggest that pharmacological inhibition of PTP1B would improve liver regeneration in patients with acute or chronic liver injury.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Revuelta-Cervantes
authors.forename: Rafael
authors.initials: R
authors.lastname: Mayoral
authors.forename: Soledad
authors.initials: S
authors.lastname: Miranda
authors.forename: Agueda
authors.initials: A
authors.lastname: González-Rodríguez
authors.forename: Margarita
authors.initials: M
authors.lastname: Fernández
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.forename: Angela M
authors.initials: AM
authors.lastname: Valverde
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D000410:Alanine Transaminase; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1