Document Detail


Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.
MedLine Citation:
PMID:  22101433     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Christian M Metallo; Paulo A Gameiro; Eric L Bell; Katherine R Mattaini; Juanjuan Yang; Karsten Hiller; Christopher M Jewell; Zachary R Johnson; Darrell J Irvine; Leonard Guarente; Joanne K Kelleher; Matthew G Vander Heiden; Othon Iliopoulos; Gregory Stephanopoulos
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-11-20
Journal Detail:
Title:  Nature     Volume:  481     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-19     Completed Date:  2012-03-06     Revised Date:  2013-07-17    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  380-4     Citation Subset:  IM    
Affiliation:
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetyl Coenzyme A / biosynthesis,  metabolism
Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
Basic Helix-Loop-Helix Transcription Factors / genetics,  metabolism
CD8-Positive T-Lymphocytes / cytology
Carbon / metabolism
Carcinoma, Renal Cell / metabolism,  pathology
Cell Hypoxia*
Cell Line, Tumor
Cells, Cultured
Citric Acid Cycle
Glutamine / metabolism*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Isocitrate Dehydrogenase / deficiency,  genetics,  metabolism*
Ketoglutaric Acids / metabolism
Kidney Neoplasms / metabolism,  pathology
Lipogenesis*
Oxidation-Reduction
Oxygen / metabolism
Palmitic Acid / metabolism
Von Hippel-Lindau Tumor Suppressor Protein / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
R01 CA122591/CA/NCI NIH HHS; R01 CA122591/CA/NCI NIH HHS; R01 DK075850-01/DK/NIDDK NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/ARNT protein, human; 0/Basic Helix-Loop-Helix Transcription Factors; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Ketoglutaric Acids; 0/endothelial PAS domain-containing protein 1; 138391-32-9/Aryl Hydrocarbon Receptor Nuclear Translocator; 328-50-7/alpha-ketoglutaric acid; 56-85-9/Glutamine; 57-10-3/Palmitic Acid; 72-89-9/Acetyl Coenzyme A; 7440-44-0/Carbon; 7782-44-7/Oxygen; EC 1.1.1.41/Isocitrate Dehydrogenase; EC 1.1.1.42./IDH1 protein, human; EC 6.3.2.19/VHL protein, human; EC 6.3.2.19/Von Hippel-Lindau Tumor Suppressor Protein
Comments/Corrections

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