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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetyl Coenzyme A / biosynthesis
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Acetyl Coenzyme A / metabolism
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Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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CD8-Positive T-Lymphocytes / cytology
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Carbon / metabolism
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / pathology
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Cell Hypoxia*
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Cell Line, Tumor
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Cells, Cultured
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Citric Acid Cycle
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Glutamine / metabolism*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Isocitrate Dehydrogenase / deficiency
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Isocitrate Dehydrogenase / genetics
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Isocitrate Dehydrogenase / metabolism*
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Ketoglutaric Acids / metabolism
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Lipogenesis*
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Oxidation-Reduction
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Oxygen / metabolism
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Palmitic Acid / metabolism
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
Substances
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ARNT protein, human
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Basic Helix-Loop-Helix Transcription Factors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Ketoglutaric Acids
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Glutamine
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Aryl Hydrocarbon Receptor Nuclear Translocator
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endothelial PAS domain-containing protein 1
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Palmitic Acid
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Acetyl Coenzyme A
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Carbon
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Isocitrate Dehydrogenase
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IDH1 protein, human
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human
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Oxygen