Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Fatty acid carbon is essential for dNTP synthesis in endothelial cells

Nature volume 520, pages 192–197 (2015)Cite this article

Subjects

A Corrigendum to this article was published on 05 August 2015

This article has been updated

Abstract

The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: FAO stimulates vessel sprouting via EC proliferation.
Figure 2: CPT1A gene deletion in ECs causes vascular defects in vivo.
Figure 3: CPT1A silencing does not cause ATP depletion or redox imbalance.
Figure 4: CPT1A silencing reduces TCA replenishment and FAO is used for nucleotide synthesis.
Figure 5: Acetate or nucleosides rescue the CPT1AKD sprouting defect.
Figure 6: Most other cell types do not use fatty acid carbons for dNTP synthesis, and inhibition of CPT1A impairs angiogenesis.

Similar content being viewed by others

Change history

References

  1. Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011)

    Article  CAS  Google Scholar 

  2. Ausprunk, D. H. & Folkman, J. Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc. Res. 14, 53–65 (1977)

    Article  CAS  Google Scholar 

  3. Welti, J., Loges, S., Dimmeler, S. & Carmeliet, P. Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J. Clin. Invest. 123, 3190–3200 (2013)

    Article  CAS  Google Scholar 

  4. De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651–663 (2013)

    Article  CAS  Google Scholar 

  5. De Bock, K., Georgiadou, M. & Carmeliet, P. Role of endothelial cell metabolism in vessel sprouting. Cell Metab. 18, 634–647 (2013)

    Article  CAS  Google Scholar 

  6. Colavitti, R. et al. Reactive oxygen species as downstream mediators of angiogenic signaling by vascular endothelial growth factor receptor-2/KDR. J. Biol. Chem. 277, 3101–3108 (2002)

    Article  CAS  Google Scholar 

  7. Fendt, S. M. et al. Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells. Nat. Commun. 4, 2236 (2013)

    Article  ADS  Google Scholar 

  8. Vander Heiden, M. G. Exploiting tumor metabolism: challenges for clinical translation. J. Clin. Invest. 123, 3648–3651 (2013)

    Article  CAS  Google Scholar 

  9. Thompson, C. B. Wnt meets Warburg: another piece in the puzzle? EMBO J. 33, 1420–1422 (2014)

    Article  CAS  Google Scholar 

  10. Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nature Rev. Cancer 13, 227–232 (2013)

    Article  CAS  Google Scholar 

  11. Henry, T. D., Satran, D. & Jolicoeur, E. M. Treatment of refractory angina in patients not suitable for revascularization. Nature Rev. Cardiol. 11, 78–95 (2014)

    Article  CAS  Google Scholar 

  12. Morris, G. W., Iams, T. A., Slepchenko, K. G. & McKee, E. E. Origin of pyrimidine deoxyribonucleotide pools in perfused rat heart: implications for 3′-azido-3′-deoxythymidine-dependent cardiotoxicity. Biochem. J. 422, 513–520 (2009)

    Article  CAS  Google Scholar 

  13. Fairbanks, L. D., Bofill, M., Ruckemann, K. & Simmonds, H. A. Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. Disproportionate expansion of pyrimidine pools and contrasting effects of de novo synthesis inhibitors. J. Biol. Chem. 270, 29682–29689 (1995)

    Article  CAS  Google Scholar 

  14. Lunt, S. Y. et al. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol. Cell 57, 95–107 (2015)

    Article  CAS  Google Scholar 

  15. Cheung, E. C. et al. TIGAR is required for efficient intestinal regeneration and tumorigenesis. Dev. Cell 25, 463–477 (2013)

    Article  CAS  Google Scholar 

  16. Jaffe, E. A., Nachman, R. L., Becker, C. G. & Minick, C. R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J. Clin. Invest. 52, 2745–2756 (1973)

    Article  CAS  Google Scholar 

  17. Michieli, P. et al. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 6, 61–73 (2004)

    Article  CAS  Google Scholar 

  18. Carlotti, F. et al. Lentiviral vectors efficiently transduce quiescent mature 3T3-L1 adipocytes. Mol. Ther. 9, 209–217 (2004)

    Article  CAS  Google Scholar 

  19. Geudens, I. et al. Role of delta-like-4/Notch in the formation and wiring of the lymphatic network in zebrafish. Arterioscler. Thromb. Vasc. Biol. 30, 1695–1702 (2010)

    Article  CAS  Google Scholar 

  20. Korff, T., Krauss, T. & Augustin, H. G. Three-dimensional spheroidal culture of cytotrophoblast cells mimics the phenotype and differentiation of cytotrophoblasts from normal and preeclamptic pregnancies. Exp. Cell Res. 297, 415–423 (2004)

    Article  CAS  Google Scholar 

  21. Schoors, S. et al. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab. 19, 37–48 (2014)

    Article  CAS  Google Scholar 

  22. Carmeliet, P. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature Med. 7, 575–583 (2001)

    Article  CAS  Google Scholar 

  23. Dagher, Z., Ruderman, N., Tornheim, K. & Ido, Y. Acute regulation of fatty acid oxidation and amp-activated protein kinase in human umbilical vein endothelial cells. Circ. Res. 88, 1276–1282 (2001)

    Article  CAS  Google Scholar 

  24. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011)

    Article  CAS  Google Scholar 

  25. Aragonés, J. et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nature Genet. 40, 170–180 (2008)

    Article  Google Scholar 

  26. Fendt, S. M. et al. Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res. 73, 4429–4438 (2013)

    Article  CAS  Google Scholar 

  27. Antoniewicz, M. R., Kelleher, J. K. & Stephanopoulos, G. Elementary metabolite units (EMU): a novel framework for modeling isotopic distributions. Metab. Eng. 9, 68–86 (2007)

    Article  CAS  Google Scholar 

  28. Fernandez, C. A., Des Rosiers, C., Previs, S. F., David, F. & Brunengraber, H. Correction of 13C mass isotopomer distributions for natural stable isotope abundance. J. Mass Spectrom. 31, 255–262 (1996)

    Article  ADS  CAS  Google Scholar 

  29. Nanchen, A., Fuhrer, T. & Sauer, U. Determination of metabolic flux ratios from 13C-experiments and gas chromatography-mass spectrometry data: protocol and principles. Methods Mol. Biol. 358, 177–197 (2007)

    Article  CAS  Google Scholar 

  30. Wilson, P. M. et al. A novel fluorescence-based assay for the rapid detection and quantification of cellular deoxyribonucleoside triphosphates. Nucleic Acids Res. 39, e112 (2011)

    Article  ADS  CAS  Google Scholar 

  31. Sakaue-Sawano, A. et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 132, 487–498 (2008)

    Article  CAS  Google Scholar 

  32. Millard, P., Letisse, F., Sokol, S. & Portais, J. C. IsoCor: correcting MS data in isotope labeling experiments. Bioinformatics 28, 1294–1296 (2012)

    Article  CAS  Google Scholar 

  33. Büscher, J. M., Czernik, D., Ewald, J. C., Sauer, U. & Zamboni, N. Cross-platform comparison of methods for quantitative metabolomics of primary metabolism. Anal. Chem. 81, 2135–2143 (2009)

    Article  Google Scholar 

  34. Benedito, R. et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137, 1124–1135 (2009)

    Article  CAS  Google Scholar 

  35. Scott, A. & Fruttiger, M. Oxygen-induced retinopathy: a model for vascular pathology in the retina. Eye 24, 416–421 (2010)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Vander Heiden and D. Tollervey for discussion, R. Adams for providing VE-cadherin(PAC)-CreERT2 mice, and S. Rodríguez-Arístegui for synthesis of etomoxir. S.S. is funded by the Institution of Research/Innovation (IWT); R.M., B.G., A.R.C. and J.G. by the Research Foundation Flanders (FWO); U.B. by a Marie Curie-IEF Fellowship; K.C.S.Q. by CAPES (Brazil) and G.B. by KU Leuven. The work of S.-M.F. is supported by Marie Curie CIG, FWO-OdysseusII, Concern Foundation, Bayer Healthcare Pharmaceuticals. The work of P.C. is supported by IUAP7/03, Methusalem funding (Flemish Government), FWO grants, Foundation Leducq Transatlantic Network (ARTEMIS), Foundation against Cancer, European Research Council (ERC) Advanced Research Grant (EU-ERC269073) and AXA Research grant. S.Y.L. was supported by the Department of Defense CDMRP Visionary Postdoctoral Award (W81XWH-12-1-0466). Views and opinions of, and endorsements by, the authors do not reflect those of the US Army or the Department of Defense. The authors thank the MSU LC-MS Core.

Author information

Author notes

  1. Sandra Schoors and Ulrike Bruning: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Laboratory of Angiogenesis and Neurovascular link, KU Leuven, B-3000 Leuven, Belgium,

    Sandra Schoors, Ulrike Bruning, Rindert Missiaen, Karla C. S. Queiroz, Gitte Borgers, Annalisa Zecchin, Anna Rita Cantelmo, Jermaine Goveia, Lucica Goddé, Stefan Vinckier, Guy Eelen, Luc Schoonjans, Mieke Dewerchin, Katrien De Bock, Bart Ghesquière & Peter Carmeliet

  2. Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium,

    Sandra Schoors, Ulrike Bruning, Rindert Missiaen, Karla C. S. Queiroz, Gitte Borgers, Annalisa Zecchin, Anna Rita Cantelmo, Jermaine Goveia, Lucica Goddé, Stefan Vinckier, Guy Eelen, Luc Schoonjans, Mieke Dewerchin, Katrien De Bock, Bart Ghesquière & Peter Carmeliet

  3. Department of Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven, B-3000 Leuven, Belgium,

    Ilaria Elia, Stefan Christen & Sarah-Maria Fendt

  4. Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, B-3000 Leuven, Belgium,

    Ilaria Elia, Stefan Christen & Sarah-Maria Fendt

  5. Department of Cardiovascular Research, Center for Molecular & Vascular Biology, KU Leuven,

    Ward Heggermont

  6. Division of Clinical Cardiology, UZ Leuven, B-3000 Leuven, Belgium,

    Ward Heggermont

  7. Laboratory of Lipid Biochemistry and Protein Interactions, KU Leuven, B-3000 Leuven, Belgium,

    Paul P. Van Veldhoven

  8. Department of Oncology, Vascular Patterning Laboratory, KU Leuven, B-3000 Leuven, Belgium,

    Holger Gerhardt

  9. Vascular Patterning Laboratory, Vesalius Research Center, VIB, B-3000 Leuven, Belgium,

    Holger Gerhardt

  10. Integrative Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine, Berlin, 13125, Germany

    Holger Gerhardt

  11. Department of Pharmaceutical and Pharmacological Sciences, Laboratory of Cell Metabolism, KU Leuven, B-3000 Leuven, Belgium,

    Myriam Baes

  12. Department of Kinesiology, Exercise Physiology Research Group, KU Leuven, B-3001 Leuven, Belgium,

    Katrien De Bock

  13. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, 48824, Michigan, USA

    Sophia Y. Lunt

Authors
  1. Sandra Schoors
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ulrike Bruning
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rindert Missiaen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karla C. S. Queiroz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gitte Borgers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ilaria Elia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Annalisa Zecchin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anna Rita Cantelmo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stefan Christen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jermaine Goveia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ward Heggermont
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lucica Goddé
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Stefan Vinckier
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Paul P. Van Veldhoven
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Guy Eelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Luc Schoonjans
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Holger Gerhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Mieke Dewerchin
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Myriam Baes
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Katrien De Bock
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Bart Ghesquière
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Sophia Y. Lunt
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Sarah-Maria Fendt
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Peter Carmeliet
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.S., U.B., R.M., K.C.S.Q., G.B., I.E., A.Z., A.R.C., S.C., J.G., W.H., L.G., S.V., P.P.V.V., G.E., L.S., M.D., M.B., K.D.B., B.G., S.Y.L., S.-M.F. and P.C. contributed to the performance of the experiments and/or analysis of the data; H.G. provided advice; S.S., U.B., K.D.B., S.M.F. and P.C. designed the experiments; S.S., M.D., K.D.B., S.M.F. and P.C. wrote the paper; S.M.F. and P.C. conceptualized the metabolic analysis, and P.C. conceived and directed the study. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Sarah-Maria Fendt or Peter Carmeliet.

Ethics declarations

Competing interests

P.C. declares to be named as inventor on patent applications, claiming subject matter related to the results described in this paper.

Extended data figures and tables

Extended Data Figure 1 FAO regulates vessel sprouting.

a, mRNA expression of CPT1 isoforms (n = 3). b, CPT1A mRNA levels upon CPT1A silencing (CPT1AKD) (n = 11). c, Representative immunoblot of CPT1A for control and CPT1AKD ECs. d, FAO flux upon CPT1A silencing in venous (HUV) and arterial (HA) ECs, or upon small interference RNA transfection in venous ECs (siRNA) (n = 6 for HUV shRNA, n = 3 for HA shRNA and HUV siRNA). e, Schematic representation of FAO measurement using [9,10-3H]palmitate (reprinted from Immunity 35, Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation, 871–882 (2011), with permission from Elsevier; ref. 24). f, Representative immunoblot for CPT1A upon genetic silencing of CPT1A using siRNA (siCPT1A). g, FAO flux upon silencing of CPT1C (CPT1CKD) (n = 3; P = NS). h, FAO flux levels in venous (HUV), arterial (HA) and microvascular (HMV) ECs (n = 4 for HUV versus HA and n = 3 for HUV versus HMV). i, Sprout number in control and CPT1AKD EC spheroids with mitomycin C (MitoC) treatment as indicated (n = 3). j, Flow cytometry counting of viable control and CPT1AKD ECs (n = 3). k, Analysis of random cell-motility tracks in control and CPT1AKD ECs (n = 4; P = NS). l, FAO flux and proliferation upon silencing of ACADVL (ACADVLKD) (n = 3 for each). m, Wound closure in control and ACADVLKD ECs (n = 3; P = NS). n, o, Quantification of vessel sprouting in control and ACADVLKD EC spheroids with MitoC treatment as indicated, total sprout length (n) and sprout numbers per spheroid (o) (n = 5). p, Sprout number in control and CPT1AOE EC spheroids with MitoC treatment as indicated (n = 3). q, Total sprout length in control and CPT1AOE EC spheroids treated with MitoC as indicated (n = 5). r, s, Representative phase (original magnification, 10× magnification) contrast images of control (r) and CPT1AOE (s) EC spheroids. t, Scratch wound assay in control and CPT1AOE ECs treated with MitoC as indicated (n = 3; P = NS). u, PCR analysis of genomic DNA from WT and CPT1AΔEC pups, confirming Cre-mediated recombination of the floxed Cpt1a allele as shown by the appearance of a 300-bp band. v, NG2+ area in neonatal vascular plexus of WT and CPT1AΔEC mice (3 litters, n = 8 pups for WT and 7 pups for CPT1AΔEC; P = NS). Data are mean ± s.e.m. of n independent experiments (a, b, d, g–q, t) or the total number of mice (v). Statistical test: mixed models. NS, not significant. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Extended Data Figure 2 CPT1A silencing does not cause cellular distress.

a, ADP/ATP ratio in control and CPT1AKD ECs (n = 3; P = NS). b, Sprout number upon oligomycin treatment (oligo) in control and CPT1AKD EC spheroids (n = 3). c, Glycolysis measurement in control and CPT1AKD ECs (n = 3; P = NS). d, Representative immunoblot for phosphorylated AMPK (pAMPK) and total AMPK (AMPK) and for LC3b I and II in control and CPT1AKD ECs. The ratio of the densitometrically quantified bands of pAMPK/AMPK and LC3b II/I is shown below the blots (n = 3; P = NS). e, Sprout number upon N-acetyl-cysteine (NAC) treatment in control and CPT1AKD EC spheroids (n = 3). f, g, Representative images (original magnification, 10×) of EC spheroids upon staining for TO-PRO3 in control (f) and CPT1AKD spheroids (g). h, i, Representative pictures (original magnification, 10×) of Hoechst/cleaved-caspase-3-stained control (h) and CPT1AKD (i) ECs. j, Representative immunoblots showing the ratio of phosphorylated (pATM)/total-ATM (ATM), p21/lamin and p53/lamin in control and CPT1AKD ECs. The ratios of the densitometrically quantified bands are shown below the blots (n = 3; P = NS). Data are mean ± s.e.m. of n independent experiments (a–e, j). Statistical test: mixed models. NS, not significant. ****P < 0.0001.

Extended Data Figure 3 FAO is used for de novo nucleotide synthesis.

a, Schematic representation of the different carbon sources used for de novo synthesis of UMP. Note that palmitate contributes three carbons to the nine carbon skeleton of UMP. PRPP, 5-phosphoribosyl-1-pyrophosphate. b, Sprout number upon 5-fluorouracil (5FU) treatment in control and CPT1AKD EC spheroids (n = 4). c, Sprout number upon methotrexate (MTX) treatment in control and CPT1AKD EC spheroids (n = 4). d, Sprout number upon acetate treatment in control and CPT1AKD EC spheroids (n = 3). e–g, Representative images (original magnification, 10×) of EC spheroids upon acetate treatment. h, i, Rescue of the sprouting defect of CPT1AKD spheroids by acetate was not affected by oligomycin treatment; panel h, total sprout length; panel i, sprout numbers/spheroid (n = 3; P = NS). j, k, Quantification of vessel sprouting using the EC spheroid model, showing that the reduction of total sprout length (j) and number of sprouts per spheroid (k) upon CPT1A silencing (CPT1AKD) was rescued by supplementation with a dNTP mix (n = 3). l, Quantification of MitoC-treated EC spheroid sprouting upon acetate or nucleoside mix supplementation (n = 3; P = NS). m, Glucose oxidation in ECs, measured by 14CO2 formation from [6-14C]glucose in control and CPT1AKD ECs (n = 4). n, Glutamine oxidation in ECs, measured by 14CO2 formation from [U-14C]glutamine in control and CPT1AKD ECs (n = 4; P = NS). o, Total contribution of [U-13C]glucose and [U-13C]glutamine to aspartate in control and CPT1AKD ECs (n = 3). p, [8-14C]hypoxanthine incorporation in RNA and DNA in control ECs (n = 3). Data are mean ± s.e.m. of n independent experiments (b–d, h–p). Statistical test: mixed models. NS, not significant. *P < 0.05, **P < 0.01, ****P < 0.0001.

Extended Data Figure 4 Etomoxir reduces vessel sprouting.

a, FAO flux upon etomoxir (Eto) treatment (n = 6). b, [3H]thymidine incorporation upon etomoxir treatment (n = 5). c, Scratch wound assay using MitoC-treated ECs upon etomoxir (Eto) treatment (n = 4; P = NS). d, Branch point quantification in the retinal vasculature of control (Ctrl) and etomoxir-treated (Eto) pups (8 litters, n = 24 pups for control and 16 for etomoxir treatment). e, f, Representative confocal images (original magnification, 10×) of retinal vessels stained for isolectin-B4 in control (e) and etomoxir (f) treated pups. g, Filopodia quantification in the retinal vascular front of control and etomoxir (Eto) treated pups (4 litters, n = 11 for WT and 9 for etomoxir; P = NS). Data are mean ± s.e.m. of n independent experiments (a–d, g) or the total number of mice (d, g). Statistical test: mixed models. NS, not significant. ****P < 0.0001.

Extended Data Figure 5 Analysis of steady state.

Percentage M+2 or M+4 citrate and aspartate over different time points (24, 36, 48 and 52 h) after labelling with [U-13C]glucose (a), [U-13C]glutamine (b), or [U-13C]palmitate (c). Data are mean ± s.d. of n = 3 independent experiments.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schoors, S., Bruning, U., Missiaen, R. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192–197 (2015). https://doi.org/10.1038/nature14362

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature14362

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing