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- Title
Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells.
- Authors
Hitzel, Juliane; Eunjee Lee; Yi Zhang; Bibli, Sofia Iris; Xiaogang Li; Zukunft, Sven; Pflüger, Beatrice; Jiong Hu; Schürmann, Christoph; Vasconez, Andrea Estefania; Oo, James A.; Kratzer, Adelheid; Kumar, Sandeep; Rezende, Flávia; Josipovic, Ivana; Thomas, Dominique; Giral, Hector; Schreiber, Yannick; Geisslinger, Gerd; Fork, Christian
- Abstract
Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
- Subjects
ENDOTHELIAL cells; PURINE nucleotides; PHOSPHOLIPIDS; SINGLE nucleotide polymorphisms; HYDROLASES; AMINO acid metabolism; GENE regulatory networks; GLYCINE receptors
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-04602-0