Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation

Karim Bensaad; Elena Favaro; Caroline A Lewis; Barrie Peck; Simon Lord; Jennifer M Collins; Katherine E Pinnick; Simon Wigfield; Francesca M Buffa; Ji-Liang Li; Qifeng Zhang; Michael J O Wakelam; Fredrik Karpe; Almut Schulze; Adrian L Harris

doi:10.1016/j.celrep.2014.08.056

Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation

Cell Rep. 2014 Oct 9;9(1):349-365. doi: 10.1016/j.celrep.2014.08.056. Epub 2014 Sep 25.

Authors

Affiliations

¹ 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.
² CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
³ Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
⁴ Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
⁵ The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
⁶ 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.
⁷ 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.

PMID: 25263561
DOI: 10.1016/j.celrep.2014.08.056

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Hypoxia / physiology
Cell Line, Tumor
Cell Proliferation / physiology
Fatty Acids / metabolism*
Glioblastoma
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Lipid Metabolism*
Oxidation-Reduction
Oxygen / metabolism*

Substances

Fatty Acids
Hypoxia-Inducible Factor 1, alpha Subunit
Oxygen

Abstract

Publication types

MeSH terms

Substances

Grants and funding