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Protein tyrosine phosphatase 1B modulates GSK3β/Nrf2 and IGFIR signaling pathways in acetaminophen-induced

M A Mobasher1, A González-Rodriguez, B Santamaría

  • 1Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain.

Cell Death & Disease
|May 11, 2013
PubMed

Insights

Protein tyrosine phosphatase 1B (PTP1B) exacerbates acetaminophen (APAP)-induced liver injury by promoting cell death. Inhibiting PTP1B protects against APAP hepatotoxicity, offering a potential therapeutic strategy.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Toxicology

Background:

  • Acetaminophen (APAP) poisoning causes acute liver failure with high mortality.
  • Protein tyrosine phosphatase 1B (PTP1B) regulates growth factor signaling and liver injury.
  • The role of PTP1B in APAP-induced liver injury is not well understood.

Purpose of the Study:

  • To investigate PTP1B expression in APAP-induced liver failure.
  • To determine PTP1B's role in hepatocyte cell death and survival pathways.
  • To evaluate PTP1B as a therapeutic target for APAP hepatotoxicity.

Main Methods:

  • Assessed PTP1B expression in human liver tissue and hepatocytes.
  • Utilized primary human and mouse hepatocytes, and a mouse model of APAP hepatotoxicity.
  • Examined signaling pathways including JNK, p38 MAPK, Akt, and Nrf2.
  • Investigated the effects of PTP1B deficiency and RNA interference.

Main Results:

  • PTP1B expression was increased in APAP-induced human liver failure.
  • APAP upregulated PTP1B, activating pro-apoptotic kinases (JNK, p38 MAPK) and decreasing anti-apoptotic factors.
  • PTP1B deficiency protected hepatocytes by enhancing antioxidant defense and maintaining growth factor signaling, reducing APAP hepatotoxicity in mice.

Conclusions:

  • PTP1B is a key mediator in APAP-induced hepatotoxicity.
  • PTP1B promotes hepatocyte death by modulating critical signaling pathways.
  • Targeting PTP1B represents a promising therapeutic approach for acetaminophen overdose.

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