title: Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.
abstract: Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
authors.forename: Paulo A
authors.initials: PA
authors.lastname: Gameiro
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Mattaini
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Yang
authors.forename: Karsten
authors.initials: K
authors.lastname: Hiller
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jewell
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Johnson
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Kelleher
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Othon
authors.initials: O
authors.lastname: Iliopoulos
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
mesh_terms: D000105:Acetyl Coenzyme A / Q000096:biosynthesis / Q000378:metabolism; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002244:Carbon / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002952:Citric Acid Cycle; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D050155:Lipogenesis; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D019308:Palmitic Acid / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000105:Acetyl Coenzyme A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D002244:Carbon; D005973:Glutamine; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007521:Isocitrate Dehydrogenase; D007656:Ketoglutaric Acids; D010100:Oxygen; D019308:Palmitic Acid; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human; C497442:HIF1A protein, human; C543588:IDH1 protein, human; C497446:VHL protein, human
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