Acute acetaminophen intoxication leads to hepatic iron loading by decreased hepcidin synthesis.
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SourceToxicological Sciences, 129, 1, (2012), pp. 225-233
1 september 2012
Article / Letter to editor
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Laboratory of Genetic, Endocrine and Metabolic Diseases
SubjectIGMD 7: Iron metabolism N4i 1: Pathogenesis and modulation of inflammation; IGMD 7: Iron metabolism ONCOL 5: Aetiology, screening and detection; NCMLS 3: Tissue engineering and pathology N4i 4: Auto-immunity, transplantation and immunotherapy; NCMLS 5: Membrane transport and intracellular motility; NCMLS 5: Membrane transport and intracellular motility IGMD 9: Renal disorder
Acetaminophen (APAP), a major cause of acute liver injury in the Western world, is mediated by metabolism and oxidative stress. Recent studies have suggested a role for iron in potentiating APAP-induced liver injury although its regulatory mechanism is not completely understood. The current study was designed to unravel the iron-regulating pathways in mice after APAP-induced hepatotoxicity. Mice with severe injury showed a significant increase in liver iron concentration and oxidative stress. Concurrently, the plasma concentration of hepcidin, the key regulator in iron metabolism, and hepatic hepcidin antimicrobial peptide (Hamp) mRNA expression levels were significantly reduced. We showed that hepcidin transcription was inhibited via several hepcidin-regulating factors, including the bone morphogenetic protein/small mother against decapentaplegic (BMP/SMAD) pathway, CCAAT/enhancer-binding protein alpha (C/EBPalpha), and possibly also via erythropoietin (EPO). Downregulation of the BMP/SMAD signaling pathway was most likely caused by hypoxia-inducible factor 1alpha (HIF-1alpha), which was increased in mice with severe APAP-induced liver injury. HIF-1alpha stimulates cleaving of hemojuvelin, the cofactor of the BMP receptor, thereby blocking BMP-induced signaling. In addition, gene expression levels of C/ebpalpha were significantly reduced, and Epo mRNA expression levels were significantly increased after APAP intoxication. These factors are regulated through HIF-1alpha during oxidative stress and suggest that HIF-1alpha is a key modulator in reduced hepcidin transcription after APAP-induced hepatotoxicity. In conclusion, acute APAP-induced liver injury leads to activation of HIF-1alpha, which results in a downregulation in hepcidin expression through a BMP/SMAD signaling pathway and through C/EBPalpha inhibition. Eventually, this leads to hepatic iron loading associated with APAP cytotoxicity.
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