The role of hypoxia-inducible factor-1α in acetaminophen hepatotoxicity

• Published in: The Journal of pharmacology and experimental therapeutics 2011-08, Vol.338 (2), p.492-502
• Main Authors: Sparkenbaugh, Erica M, Saini, Yogesh, Greenwood, Krista K, LaPres, John J, Luyendyk, James P, Copple, Bryan L, Maddox, Jane F, Ganey, Patricia E, Roth, Robert A
• Format: Article
• Language: English
• Subjects: Acetaminophen - toxicity; Animals; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Chemical and Drug Induced Liver Injury - prevention & control; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Oxidative Stress - drug effects; Oxidative Stress - physiology; Toxicology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.111.180521

Hypoxia-inducible factor-1α (HIF-1α) is a critical transcription factor that controls oxygen homeostasis in response to hypoxia, inflammation, and oxidative stress. HIF has been implicated in the pathogenesis of liver injury in which these events play a role, including acetaminophen (APAP) overdose, which is the leading cause of acute liver failure in the United States. APAP overdose has been reported to activate HIF-1α in mouse livers and isolated hepatocytes downstream of oxidative stress. HIF-1α signaling controls many factors that contribute to APAP hepatotoxicity, including mitochondrial cell death, inflammation, and hemostasis. Therefore, we tested the hypothesis that HIF-1α contributes to APAP hepatotoxicity. Conditional HIF-1α deletion was generated in mice using an inducible Cre-lox system. Control (HIF-1α-sufficient) mice developed severe liver injury 6 and 24 h after APAP overdose (400 mg/kg). HIF-1α-deficient mice were protected from APAP hepatotoxicity at 6 h, but developed severe liver injury by 24 h, suggesting that HIF-1α is involved in the early stage of APAP toxicity. In further studies, HIF-1α-deficient mice had attenuated thrombin generation and reduced plasminogen activator inhibitor-1 production compared with control mice, indicating that HIF-1α signaling contributes to hemostasis in APAP hepatotoxicity. Finally, HIF-1α-deficient animals had decreased hepatic neutrophil accumulation and plasma concentrations of interleukin-6, keratinocyte chemoattractant, and regulated upon activation normal T cell expressed and secreted compared with control mice, suggesting an altered inflammatory response. HIF-1α contributes to hemostasis, sterile inflammation, and early hepatocellular necrosis during the pathogenesis of APAP toxicity.