Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nature (Impact Factor: 41.46). 11/2011; 481(7381):380-4. DOI: 10.1038/nature10602
Source: PubMed


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.

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    • "Under normoxia, up to 25% of fatty acid carbons are derived from glutamine, while up to 80% are glutamine-derived under hypoxia. Reductive carboxylation of glutamine-derived a-ketoglutarate mediated by IDH enzymes contributes to acetyl-CoA synthesis for lipogenesis [Metallo et al., 2011]. However, further analysis demonstrated that fatty acid labeling from glutamine could be explained by isotope exchange without net reductive IDH flux [Fan et al., 2013]. "
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