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Essential role of Protein Tyrosine Phosphatase 1B in the modulation of insulin signaling by acetaminophen in hepatocytes

AuthorsMobasher, Maysa A.; Toro Martín, Juan de; González-Rodríguez, Águeda; Ramos, Sonia ; Letzig, Lynda G.; James, Laura P.; Muntané, Jordi; Álvarez, Carmen; Valverde, Ángela M.
Issue Date7-Nov-2014
CitationCNIC Conference: Energy homeostasis and metabolic disease (2014)
Abstract[Objectives]: The metabolic adverse effects of drugs develop slowly and are often missed in safety protocols, toxicity or clinical assays. In this regard, many drugs are associated with the development of glucose intolerance or deterioration in glycemic control in patients with pre-existing diabetes. Acetaminophen (APAP) has been used for over 40 years as an analgesic in the treatment of acute and chronic pain. We have investigated the cross-talk between signaling pathways activated by APAP and insulin signaling in hepatocytes with or without expression of the protein tyrosine phosphatase IB (PTPIB) and in wild-type and PTPIB-deficient mice chronically treated with APAP. [Methods]: Human primary hepatocytes, Huh7 hepatoma cells with silenced PTPIB, mouse hepatocytes from wild-type and PTPIB-deficient mice and a mouse model of chronic APAP treatment were used to examine the mechanisms involving PTPIB in the effects of APAP on glucose homeostasis and hepatic insulin signaling. Energy expenditure and islet alpha/beta cell ratio were also evaluated. [Results]: In APAP-treated human and mouse hepatocytes at concentrations that did not induce death, phosphorylation of c-jun (NH2) terminal kinase (JNK) and PTPlB expression and activity were increased. APAP pretreatment inhibited the early steps of insulin signaling and decreased Akt phosphorylation. Rosiglitazone prevented APAP effects in insulin signaling by decreasing JNK phosphorylation and PTPIB levels. Likewise, PTPIB deficiency in human or mouse hepatocytes protected against APAP-mediated impairment hepatic insulin signaling. These signaling pathways were modulated in mice with chronic APAP treatment with a protection against APAP-mediated hepatic insulin resistance and alterations in islet alpha/beta cell ratio in PTPIB-1- mice. [Conclusions]: our results have demonstrated a negative cross-talk between signaling pathways triggered by APAP and insulin signaling in hepatocytes, which is in part mediated by PTPIB. Moreover, our in vivo data suggest taht chronic use o fAPAP may be associated with insulin resistance in the liver.
DescriptionResumen del póster presentado a la Conferencia del Centro Nacional de Investigaciones Cardiovasculares (CNIC) titulada: "Energy homeostasis and metabolic disease", celebrada en Madrid del 7 al 8 de noviembre de 2014.
Appears in Collections:(ICTAN) Comunicaciones congresos
(IBIS) Comunicaciones congresos
(IIBM) Comunicaciones congresos
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