title: Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation.
abstract: An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.
authors.affiliation: CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK. Electronic address: karim.bensaad@imm.ox.ac.uk.
authors.forename: Karim
authors.initials: K
authors.lastname: Bensaad
authors.affiliation: CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Favaro
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lewis
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Barrie
authors.initials: B
authors.lastname: Peck
authors.affiliation: CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Lord
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Collins
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Pinnick
authors.affiliation: CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Wigfield
authors.affiliation: CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Michael J O
authors.initials: MJO
authors.lastname: Wakelam
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK; NIHR Oxford Biomedical Research Centre, OUH Trust, Churchill Hospital, Oxford OX3 7LF, UK.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK; Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Schulze
authors.affiliation: CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D005909:Glioblastoma; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D050356:Lipid Metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen