5-lipoxygenase deficiency reduces hepatic inflammation and tumor necrosis factor α–induced hepatocyte damage in hyperlipidemia-prone ApoE-null mice

Authors

  • Marcos Martínez-Clemente,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain
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  • Natàlia Ferré,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain
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  • Ana González-Périz,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain
    2. Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd) (Biomedical Research Networking Center on Liver and Digestive Disease), University of Barcelona, Barcelona, Spain
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  • Marta López-Parra,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain
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  • Raquel Horrillo,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain
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  • Esther Titos,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain
    2. Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd) (Biomedical Research Networking Center on Liver and Digestive Disease), University of Barcelona, Barcelona, Spain
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  • Eva Morán-Salvador,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain
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  • Rosa Miquel,

    1. Department of Pathology, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain
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  • Vicente Arroyo,

    1. Department of Liver Unit, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Insititut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunye Biomedical Research Institute), Barcelona, Spain
    2. Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd) (Biomedical Research Networking Center on Liver and Digestive Disease), University of Barcelona, Barcelona, Spain
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  • Colin D. Funk,

    1. Departments of Physiology and Biochemistry, Queen's University, Kingston, Ontario, Canada
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    • C. D. F. is a Tier I Canada Research Chair in Molecular, Cellular, and Physiological Medicine and a Career Investigator of the Heart and Stroke Foundation of Ontario

  • Joan Clària

    Corresponding author
    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (Esther Koplowitz Biomedical Research Center), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (August Pi i Sunyer Biomedical Research Institute), Barcelona, Spain
    2. Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd) (Biomedical Research Networking Center on Liver and Digestive Disease), University of Barcelona, Barcelona, Spain
    • Department of Biochemistry and Molecular Genetics, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain
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    • fax: (34)-93-2275454.


  • Potential conflict of interest: Nothing to report.

Abstract

The actual risk factors that drive hepatic inflammation during the transition from steatosis to steatohepatitis are unknown. We recently demonstrated that hyperlipidemia-prone apolipoprotein E–deficient (ApoE−/−) mice exhibit hepatic steatosis and increased susceptibility to hepatic inflammation and advanced fibrosis. Because the proinflammatory 5-lipoxygenase (5-LO) pathway was found to be up-regulated in these mice and given that 5-LO deficiency confers cardiovascular protection to ApoE−/− mice, we determined the extent to which the absence of 5-LO would alter liver injury in these mice. Compared with ApoE−/− mice, which showed expected hepatic steatosis and inflammation, ApoE/5-LO double-deficient (ApoE−/−/5-LO−/−) mice exhibited reduced hepatic inflammation, macrophage infiltration, tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-18 expression, caspase-3 and nuclear factor-κB (NF-κB) activities, and serum alanine aminotransferase levels in the absence of changes in hepatic steatosis. The lack of 5-LO produced a remarkable insulin-sensitizing effect in the adipose tissue because peroxisome proliferator-activated receptor γ, insulin receptor substrate-1, and adiponectin were up-regulated, whereas c-Jun amino-terminal kinase phosphorylation and MCP-1 and IL-6 expression were down-regulated. On the other hand, hepatocytes isolated from ApoE−/−/5-LO−/− mice were more resistant to TNF-α–induced apoptosis. The 5-LO products leukotriene (LT) B4, LTD4, and 5-HETE consistently triggered TNF-α–induced apoptosis and compromised hepatocyte survival by suppressing NF-κB activity in the presence of actinomycin D. Moreover, ApoE−/−/5-LO−/− mice were protected against sustained high-fat diet (HFD)-induced liver injury and hepatic inflammation, macrophage infiltration and insulin resistance were significantly milder than those of ApoE−/− mice. Finally, pharmacological inhibition of 5-LO significantly reduced hepatic inflammatory infiltrate in the HFD and ob/ob models of fatty liver disease. Conclusion: These combined data indicate that hyperlipidemic mice lacking 5-LO are protected against hepatic inflammatory injury, suggesting that 5-LO is involved in mounting hepatic inflammation in metabolic disease. (HEPATOLOGY 2010.)

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