Hypoxia inducible factor-1 alpha induction by tumour necrosis factor-alpha, but not by toll-like receptor agonists, modulates cellular respiration in cultured human hepatocytes.

Tomas Regueira, Philipp M Lepper, Sebastian Brandt, Matthias Ochs, Madhusudanarao Vuda, Jukka Takala, Stephan M Jakob, Siamak Djafarzadeh

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24 Scopus citations

Abstract

BACKGROUND/AIMS: Genes encoding for some of the mitochondrial proteins are under the control of the transcriptional factor hypoxia inducible factor-1 alpha (HIF-1 alpha), which can accumulate under normoxic conditions in inflammatory states. The aim of this study was to evaluate the effects of cobalt chloride (CoCl(2), a hypoxia mimicking agent), tumour necrosis factor-alpha (TNF-alpha) and toll-like receptor (TLR) -2, -3 and -4 agonists on HIF-1 alpha accumulation, and further on HIF-1 alpha-mediated modulation of mitochondrial respiration in cultured human hepatocytes.\n\nMETHODS: The human hepatoma cell line HepG2 was used in this study. Cells were treated with CoCl(2), TNF-alpha and TLR-2, -3 and -4 agonists. HIF-1 alpha was determined by Western blotting and mitochondrial respiration in stimulated cells by high-resolution respirometry.\n\nRESULTS: CoCl(2), TNF-alpha and TLR agonists induced the expression of HIF-1 alpha in a time-dependent fashion. TNF-alpha and CoCl(2), but not TLR agonists, induced a reduction in complex I-, II- and IV-dependent mitochondrial oxygen consumption. TNF-alpha-associated reduction of cellular oxygen consumption was abolished through inhibition of HIF-1 alpha activity by chetomin (CTM). Pretreatment with cyclosporine A prevented CoCl(2)-induced reduction of complex I- and II-dependent mitochondrial oxygen consumption and TNF-alpha-induced reduction of complex-I-dependent respiration, implicating the involvement of the mitochondrial permeability transition pore openings. TNF-alpha and TLR-2, -3 and -4 agonists induced the expression of vascular endothelial growth factor, which was partially abolished by the blockage of HIF-1 alpha with CTM.\n\nCONCLUSIONS: The data suggest that HIF-1 alpha modulates mitochondrial respiration during CoCl(2) and TNF-alpha stimulation, whereas it has no effect when induced with TLR-2, -3 and -4 agonists.
Original languageEnglish (US)
Pages (from-to)1582-92
Number of pages11
JournalLiver International
DOIs
StatePublished - Nov 2009

Keywords

  • Caspase 3
  • Caspase 3: metabolism
  • Cell Respiration
  • Cell Respiration: drug effects
  • Cobalt
  • Cobalt: pharmacology
  • Hep G2 Cells
  • Hepatocytes
  • Hepatocytes: metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hypoxia-Inducible Factor 1, alpha Subunit: biosynt
  • Mitochondrial Membrane Transport Proteins
  • Oxygen Consumption
  • Oxygen Consumption: drug effects
  • Toll-Like Receptors
  • Toll-Like Receptors: agonists
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factor-alpha: pharmacology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor A: analysis

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