Hypoxia-inducible transcription factor 2α promotes steatohepatitis through augmenting lipid accumulation, inflammation, and fibrosis

Authors

  • Aijuan Qu,

    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
    Search for more papers by this author
  • Matthew Taylor,

    1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
    Search for more papers by this author
  • Xiang Xue,

    1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
    Search for more papers by this author
  • Tsutomu Matsubara,

    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
    Search for more papers by this author
  • Daniel Metzger,

    1. Department of Physiological Genetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
    Search for more papers by this author
  • Pierre Chambon,

    1. Department of Physiological Genetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
    Search for more papers by this author
  • Frank J. Gonzalez,

    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
    Search for more papers by this author
  • Yatrik M. Shah

    Corresponding author
    1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
    2. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
    • Department of Molecular and Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, University of Michigan, 1301 East Catherine Street, Ann Arbor, MI 48109
    Search for more papers by this author
    • fax: 734-936-8813


  • Potential conflict of interest: Nothing to report.

  • This study was supported by grants from the National Institutes of Health (CA148828), The University of Michigan Gastrointestinal Peptide Center (to Y.M.S.), and the National Cancer Institute Intramural Research Program.

Abstract

Oxygen dynamics in the liver is a central signaling mediator controlling hepatic homeostasis, and dysregulation of cellular oxygen is associated with liver injury. Moreover, the transcription factor relaying changes in cellular oxygen levels, hypoxia-inducible factor (HIF), is critical in liver metabolism, and sustained increase in HIF signaling can lead to spontaneous steatosis, inflammation, and liver tumorigenesis. However, the direct responses and genetic networks regulated by HIFs in the liver are unclear. To help define the HIF signal-transduction pathway, an animal model of HIF overexpression was generated and characterized. In this model, overexpression was achieved by Von Hippel-Lindau (Vhl) disruption in a liver-specific temporal fashion. Acute disruption of Vhl induced hepatic lipid accumulation in an HIF-2α–dependent manner. In addition, HIF-2α activation rapidly increased liver inflammation and fibrosis, demonstrating that steatosis and inflammation are primary responses of the liver to hypoxia. To identify downstream effectors, a global microarray expression analysis was performed using livers lacking Vhl for 24 hours and 2 weeks, revealing a time-dependent effect of HIF on gene expression. Increase in genes involved in fatty acid synthesis were followed by an increase in fatty acid uptake-associated genes, and an inhibition of fatty acid β-oxidation. A rapid increase in proinflammatory cytokines and fibrogenic gene expression was also observed. In vivo chromatin immunoprecipitation assays revealed novel direct targets of HIF signaling that may contribute to hypoxia-mediated steatosis and inflammation. Conclusion: These data suggest that HIF-2α is a critical mediator in the progression from clinically manageable steatosis to more severe steatohepatitis and liver cancer, and may be a potential therapeutic target. (HEPATOLOGY 2011;)

Ancillary