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Protein Tyrosine Phosphatase 1B (PTP1B) deficiency accelerates hepatic regeneration in mice.
- Source :
-
The American journal of pathology [Am J Pathol] 2011 Apr; Vol. 178 (4), pp. 1591-604. Date of Electronic Publication: 2011 Mar 04. - Publication Year :
- 2011
-
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.<br /> (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Alanine Transaminase metabolism
Animals
Apoptosis
Cell Proliferation
Epidermal Growth Factor metabolism
Hepatocyte Growth Factor metabolism
Hepatocytes cytology
Interleukin-6 metabolism
Liver metabolism
Male
Mice
Mice, Inbred C57BL
Phosphorylation
Tumor Necrosis Factor-alpha metabolism
Liver pathology
Liver Regeneration
Protein Tyrosine Phosphatase, Non-Receptor Type 1 deficiency
Protein Tyrosine Phosphatase, Non-Receptor Type 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 178
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 21406170
- Full Text :
- https://doi.org/10.1016/j.ajpath.2010.12.020