Cookies help us deliver our services. By using our services, you agree to our use of cookies. More information

Regueira 2009 Liver Int

From Bioblast
Publications in the MiPMap
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.

» 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. Keywords: CTM; HIF-1α; High-resolution respirometry; Mitochondria; MyD88; TLRs; TNF-α; VEGF; HepG2

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