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Regueira 2009 Liver Int

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Regueira T, Lepper PM, Brandt S, Ochs M, Vuda M, Takala J, Jakob SM, Djafarzadeh S (2009) Hypoxia inducible factor-1alpha induction by tumour necrosis factor-alpha, but not by toll-like receptor agonists, modulates cellular respiration in cultured human hepatocytes. Liver Int 10:1582-92.

Β» PMID: 19744167

Regueira T, Lepper PM, Brandt S, Ochs M, Vuda M, Takala J, Jakob SM, Djafarzadeh S (2009) Liver Int

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 (CoCl2, 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.

METHODS: The human hepatoma cell line HepG2 was used in this study. Cells were treated with CoCl2, 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.

RESULTS: CoCl2, TNF-alpha and TLR agonists induced the expression of HIF-1 alpha in a time-dependent fashion. TNF-alpha and CoCl2, 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 CoCl2-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.

CONCLUSIONS: The data suggest that HIF-1 alpha modulates mitochondrial respiration during CoCl2 and TNF-alpha stimulation, whereas it has no effect when induced with TLR-2, -3 and -4 agonists. β€’ Keywords: CTM; HIF-1Ξ±; High-resolution respirometry; Mitochondria; MyD88; TLRs; TNF-Ξ±; VEGF; HepG2

β€’ O2k-Network Lab: CH Bern Djafarzadeh S, CL Santiago Regueira T

Labels: MiParea: Respiration 

Stress:Ischemia-reperfusion, Hypoxia  Organism: Human  Tissue;cell: Liver  Preparation: Permeabilized cells 

Coupling state: LEAK, OXPHOS  Pathway: N, S, CIV, ROX  HRR: Oxygraph-2k