Abstract
Acute hepatic failure secondary to acetaminophen (APAP) poisoning is associated with high mortality. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of tyrosine kinase growth factor signaling. In the liver, this pathway confers protection against injury. However, the involvement of PTP1B in the intracellular networks activated by APAP is unknown. We have assessed PTP1B expression in APAP-induced liver failure in humans and its role in the molecular mechanisms that regulate the balance between cell death and survival in human and mouse hepatocytes, as well as in a mouse model of APAP-induced hepatotoxicity. PTP1B expression was increased in human liver tissue removed during liver transplant from patients for APAP overdose. PTP1B was upregulated by APAP in primary human and mouse hepatocytes together with the activation of c-jun (NH2) terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), resulting in cell death. Conversely, Akt phosphorylation and the antiapoptotic Bcl2 family members BclxL and Mcl1 were decreased. PTP1B deficiency in mouse protects hepatocytes against APAP-induced cell death, preventing glutathione depletion, reactive oxygen species (ROS) generation and activation of JNK and p38 MAPK. APAP-treated PTP1B−/− hepatocytes showed enhanced antioxidant defense through the glycogen synthase kinase 3 (GSK3)β/Src kinase family (SKF) axis, delaying tyrosine phosphorylation of the transcription factor nuclear factor-erythroid 2-related factor (Nrf2) and its nuclear exclusion, ubiquitination and degradation. Insulin-like growth factor-I receptor-mediated signaling decreased in APAP-treated wild-type hepatocytes, but was maintained in PTP1B−/− cells or in wild-type hepatocytes with reduced PTP1B levels by RNA interference. Likewise, both signaling cascades were modulated in mice, resulting in less severe APAP hepatotoxicity in PTP1B−/− mice. Our results demonstrated that PTP1B is a central player of the mechanisms triggered by APAP in hepatotoxicity, suggesting a novel therapeutic target against APAP-induced liver failure.
Highlights
Overdose is the most frequent cause of drug-induced liver failure in the United States[2,3] and most of Europe.[4,5] In these countries, APAP is a leading cause of urgent liver transplantation, which accounts for considerable levels of morbidity and mortality.[2]
We investigated if protein tyrosine phosphatase 1B (PTP1B) was modulated during APAP-induced human liver injury
There is evidence of increased PTP1B expression during the progression of non-alcoholic fatty liver disease that concurs with insulin resistance and liver damage.[30,31]
Summary
Overdose is the most frequent cause of drug-induced liver failure in the United States[2,3] and most of Europe.[4,5] In these countries, APAP is a leading cause of urgent liver transplantation, which accounts for considerable levels of morbidity and mortality.[2]. Generation of reactive oxygen (ROS) and nitrogen species, lipid peroxidation, mitochondrial dysfunction, disruption of calcium homeostasis and induction of apoptosis and necrosis are involved in APAP-induced hepatotoxicity.[12,13,14] tight control of ROS levels by antioxidant molecules and detoxifying enzymes is important to restore the balance between oxidants and antioxidants in cells challenged with oxidative insults. In this regard, nuclear factor erythroid-2-related factor 2 (Nrf2) activates detoxifying enzymes by binding to antioxidant response elements (AREs). PTP1B has been proposed as a therapeutic target against type 2 diabetes and obesity via its capacity to dephosphorylate insulin and leptin receptors.[18,19] PTP1B dephosphorylates and inactivates receptors of the tyrosine kinase superfamily, such as EGF receptor, PDGF receptor,[20] hepatocyte growth factor receptor/met 21 and insulin-like growth factor-I receptor (IGFIR),[22] which are involved in hepatocyte survival.[23,24] On this basis, the aim of this study was to investigate the role of PTP1B in APAP-induced hepatotoxicity
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