title: The role of HIF-1 in oncostatin M-dependent metabolic reprogramming of hepatic cells.
abstract: BACKGROUND
  Hypoxia and inflammation have been identified as hallmarks of cancer. A majority of hepatocellular carcinomas are preceded by hepatitis B- or C-related chronic infections suggesting that liver cancer development is promoted by an inflammatory microenvironment. The inflammatory cytokine oncostatin M (OSM) was shown to induce the expression of hypoxia-inducible factor-1 α (HIF-1 α) under normoxic conditions in hepatocytes and hepatoma cells. HIF-1 α is known to orchestrate the expression of numerous genes, many of which code for metabolic enzymes that play key roles in the adaptation of cellular metabolism to low oxygen tension.
  
  
  RESULTS
  Here, we show that OSM-induced upregulation of HIF-1 α reprograms cellular metabolism in three clones of the human hepatocyte cell line PH5CH (PH5CH1, PH5CH7, and PH5CH8) towards a hypoxia-like metabolic phenotype but has no significant effect on cellular metabolism of HepG2 and JHH-4 hepatoma cells. Although we observed only minor changes in glucose uptake and lactate secretion in PH5CH8 upon OSM treatment, we identified more pronounced changes in intracellular fluxes based on stable isotope labeling experiments. In particular, glucose oxidation in the tricarboxylic acid (TCA) cycle is reduced through pyruvate dehydrogenase kinase 1 (PDK1)-mediated inhibition of the pyruvate dehydrogenase complex, thereby reducing the oxidative TCA cycle flux. As a result of the impaired mitochondrial glucose and glutamine oxidation, the reductive isocitrate dehydrogenase flux was increased.
  
  
  CONCLUSIONS
  We provide evidence that connects the inflammatory mediator OSM to a hypoxia-like metabolic phenotype. In the human hepatocyte cell line PH5CH, OSM-mediated upregulation of HIF-1 α and PDK1 can induce hypoxia-like metabolic changes, although to a lesser extent than hypoxia itself. Since PDK1 is overexpressed in several cancers, it might provide a causal link between chronic inflammation and malignant cellular transformation.
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Avenue des Hauts-Fourneaux 7, Esch-Belval, L-4362 Luxembourg.
authors.forename: Nadia
authors.initials: N
authors.lastname: Battello
authors.affiliation: Life Sciences Research Unit, University of Luxembourg, Avenue de la Fäincerie 162a, Luxembourg, 1511 Luxembourg.
authors.forename: Andreas David
authors.initials: AD
authors.lastname: Zimmer
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Avenue des Hauts-Fourneaux 7, Esch-Belval, L-4362 Luxembourg.
authors.forename: Carole
authors.initials: C
authors.lastname: Goebel
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Avenue des Hauts-Fourneaux 7, Esch-Belval, L-4362 Luxembourg.
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Dong
authors.affiliation: Life Sciences Research Unit, University of Luxembourg, Avenue de la Fäincerie 162a, Luxembourg, 1511 Luxembourg.
authors.forename: Iris
authors.initials: I
authors.lastname: Behrmann
authors.affiliation: Life Sciences Research Unit, University of Luxembourg, Avenue de la Fäincerie 162a, Luxembourg, 1511 Luxembourg.
authors.forename: Claude
authors.initials: C
authors.lastname: Haan
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Avenue des Hauts-Fourneaux 7, Esch-Belval, L-4362 Luxembourg.
authors.forename: Karsten
authors.initials: K
authors.lastname: Hiller
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Avenue des Hauts-Fourneaux 7, Esch-Belval, L-4362 Luxembourg.
authors.forename: Andre
authors.initials: A
authors.lastname: Wegner
keywords: Hypoxia-inducible factor; Inflammation; Oncostatin M; Pyruvate dehydrogenase complex; Pyruvate dehydrogenase kinase; Stable isotope labeling experiments