Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells

• Published in: Nature communications 2018-06, Vol.9 (1), p.2292-18, Article 2292
• Main Authors: Hitzel, Juliane, Lee, Eunjee, Zhang, Yi, Bibli, Sofia Iris, Li, Xiaogang, Zukunft, Sven, Pflüger, Beatrice, Hu, Jiong, 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, Yang, Xia, Sigala, Fragiska, Romanoski, Casey E., Kroll, Jens, Jo, Hanjoong, Landmesser, Ulf, Lusis, Aldons J., Namgaladze, Dmitry, Fleming, Ingrid, Leisegang, Matthias S., Zhu, Jun, Brandes, Ralf P.
• Format: Article
• Language: English
• Subjects: 13/51; 13/89; 13/95; 14/19; 38/109; 38/77; 38/88; 38/90; 38/91; 45/43; 49; 49/61; 59; 631/443/592/75/593/2100; 631/45/287/1194; 631/553/2711; 631/553/2714; 64; 64/116; 64/60; 82/58; 96/1; Adenosine triphosphate; Amino acids; Amino Acids - metabolism; Aminohydrolases - metabolism; Angiogenesis; Animals; Aorta; Aorta - cytology; Arteriosclerosis; Atherosclerosis; Atherosclerosis - metabolism; ATP; Bayes Theorem; Bayesian analysis; Cardiovascular disease; Cardiovascular Diseases - metabolism; Clusters; Coronary artery; Coronary artery disease; Disease control; Endothelial cells; Endothelial Cells - metabolism; Gene Expression Regulation; Genetic Techniques; Glycine; Glycine - chemistry; Heart diseases; Human Umbilical Vein Endothelial Cells; Humanities and Social Sciences; Humans; Lipoproteins; Metabolism; Methylenetetrahydrofolate dehydrogenase; Methylenetetrahydrofolate Dehydrogenase (NADP) - metabolism; Mitochondria; multidisciplinary; Multifunctional Enzymes - metabolism; Multigene Family; Neovascularization, Pathologic; Network analysis; Nucleotides; Nucleotides - chemistry; Oxygen - chemistry; Phospholipids; Phospholipids - chemistry; Probability; Purines; Purines - chemistry; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Serine; Single-nucleotide polymorphism; Synthesis; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04602-0

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. During atherosclerosis, endothelial cells release purines in response to oxidized phospholipids. Here, Hitzel et al. show that oxidized phospholipids activate an MTHFD2-regulated gene network in endothelial cells which reprograms amino acid metabolism towards production of purines and thus compensates for their loss.