Disruption of the 12/15-lipoxygenase gene (Alox15) protects hyperlipidemic mice from nonalcoholic fatty liver disease

Authors

  • Marcos Martínez-Clemente,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    Search for more papers by this author
  • Natàlia Ferré,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    Search for more papers by this author
  • Esther Titos,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    2. Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
    Search for more papers by this author
  • Raquel Horrillo,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    Search for more papers by this author
  • Ana González-Périz,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    2. Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
    Search for more papers by this author
  • Eva Morán-Salvador,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    Search for more papers by this author
  • Cristina López-Vicario,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    Search for more papers by this author
  • Rosa Miquel,

    1. Department of Pathology, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    Search for more papers by this author
  • Vicente Arroyo,

    1. Department of Liver Unit, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    2. Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
    Search for more papers by this author
  • Colin D. Funk,

    1. Department of Physiology and Biochemistry, Queen's University, Kingston, Canada
    Search for more papers by this author
  • Joan Clària

    Corresponding author
    1. Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigaciones Biomédicas Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    2. Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
    • Department of Biochemistry and Molecular Genetics, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain
    Search for more papers by this author
    • fax: (34)-93-2275454


  • Supported by a grant from the Ministry of Science and Innovation (MICINN) (SAF 09/08767). The Biomedical Research Networking Center on Liver and Digestive Diseases (CIBERehd) is funded by Carlos III Health Institute. Our laboratory is a consolidated research group recognized by the Generalitat de Catalunya (2009SGR1484). M. M.-C. was supported by MICINN (contract number BES-2007-16147). E. T. and A. G.-P. had contracts with CIBERehd. N. F. (Juan de la Cierva Program) and E. M.-S. were supported by MICINN. C. L.-V. was supported by August Pi i Sunyer Biomedical Research Institute. C. D. F. holds a Tier I Canada Research Chair in Molecular, Cellular, and Physiological Medicine and is a Carrer Investigator of the Heart and Stroke Foundation of Ontario.

  • Potential conflict of interest: Nothing to report.

Abstract

We have shown that Alox15, the gene encoding for 12/15-lipoxygenase (12/15-LO), is markedly up-regulated in livers from apolipoprotein E-deficient (ApoE−/−) mice, which spontaneously develop nonalcoholic fatty liver disease secondary to hyperlipidemia. In the current study, we used ApoE−/− mice with a targeted disruption of the Alox15 gene to assess the role of 12/15-LO in the development and progression of hepatic steatosis and inflammation. Compared with ApoE−/− mice, which exhibited extensive hepatic lipid accumulation and exacerbated inflammatory injury, ApoE/12/15-LO double-knockout (ApoE−/−/12/15-LO−/−) mice showed reduced serum alanine aminotransferase levels; decreased hepatic steatosis, inflammation, and macrophage infiltration; and decreased fatty acid synthase, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-18, and IL-6 expression. Remarkably, disruption of Alox15 attenuated glucose intolerance and high-fat diet-induced insulin resistance, up-regulated insulin receptor substrate-2, and exerted opposite effects on hepatic c-Jun amino-terminal kinase and adenosine monophosphate–activated protein kinase phosphorylation, known negative and positive regulators of insulin signaling, respectively. In adipose tissue, the absence of Alox15 induced significant reductions in the expression of the proinflammatory and insulin-resistant adipokines MCP-1, TNFα, and resistin while increasing the expression of glucose transporter-4. Interestingly, compared with ApoE−/− mice, which exhibited increased hepatic caspase-3 staining, ApoE−/−/12/15-LO−/− mice showed attenuated hepatocellular injury. Consistent with this finding, hepatocytes isolated from ApoE−/− mice were more vulnerable to TNFα-induced programmed cell death, an effect that was not observed in hepatocytes carrying a targeted disruption of the Alox15 gene. Conclusion: Collectively, our data suggest a potentially relevant mechanism linking 12/15-LO to the promotion of hepatic steatosis, insulin resistance, and inflammation in experimental liver disease of metabolic origin. (HEPATOLOGY 2010)

Ancillary