Publication Date:
2011-11-22
Description:
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 alpha-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 alpha-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710581/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metallo, Christian M -- Gameiro, Paulo A -- Bell, Eric L -- Mattaini, Katherine R -- Yang, Juanjuan -- Hiller, Karsten -- Jewell, Christopher M -- Johnson, Zachary R -- Irvine, Darrell J -- Guarente, Leonard -- Kelleher, Joanne K -- Vander Heiden, Matthew G -- Iliopoulos, Othon -- Stephanopoulos, Gregory -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA122591/CA/NCI NIH HHS/ -- R01 DK075850-01/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Nov 20;481(7381):380-4. doi: 10.1038/nature10602.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22101433" target="_blank"〉PubMed〈/a〉
Keywords:
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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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