The role of fatty acid β-oxidation in lymphangiogenesis

  1. Zecchin, Annalisa
  2. Blacher, Silvia
  3. Ghesquière, Bart
  4. Thienpont, Bernard
  5. Moral-Dardé, Veronica 1
  6. Huang, Hongling
  7. Zhao, Hui
  8. Brüning, Ulrike
  9. Goveia, Jermaine
  10. Shi, Chenyan
  11. Fendt, Sarah-Maria
  12. Cornelissen, Ivo
  13. García-Caballero, Melissa
  14. Hägerling, René
  15. Luttun, Aernout
  16. Kiefer, Friedemann
  17. Wong, Brian W.
  18. Knobloch, Marlen
  19. Jessberger, Sebastian
  20. Wang, Xingwu
  21. Dewerchin, Mieke
  22. Missiaen, Rindert
  23. Dierkes, Cathrin
  24. Eelen, Guy
  25. Lambrechts, Diether
  26. Vinckier, Stefan
  27. Schoonjans, Luc
  28. Wyns, Sabine
  29. Kalucka, Joanna
  30. Lippens, Martin
  31. Carmeliet, Peter
  32. Noel, Agnès
  33. Moons, Lieve
  34. Mostrar todos los/as autores/as +
  1. 1 Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center
  2. 2 KU Leuven
    info

    KU Leuven

    Lovaina, Bélgica

    ROR https://ror.org/05f950310

  3. 3 Laboratory of Translational Genetics, VIB Vesalius Research Center
  4. 4 University of Liège
    info

    University of Liège

    Lieja, Bélgica

    ROR https://ror.org/00afp2z80

  5. 5 University of Zurich
    info

    University of Zurich

    Zúrich, Suiza

    ROR https://ror.org/02crff812

  6. 6 Max Planck Institute for Molecular Biomedicine
    info

    Max Planck Institute for Molecular Biomedicine

    Münster, Alemania

    ROR https://ror.org/040djv263

  7. 7 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Vesalius Research Center
  8. 8 Center for Vascular Biology Research
    info

    Center for Vascular Biology Research

    Boston, Estados Unidos

    ROR https://ror.org/04wsv7966

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Revista:
Nature

ISSN: 0028-0836,  1476-4687

Año de publicación: 2016

Volumen: 542

Número: 7639

Páginas: 49-54

Tipo: Artículo

DOI: 10.1038/NATURE21028 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Nature

Resumen

Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid β-oxidation, impairs lymphatic development. LECs use fatty acid β-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid β-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1–p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo.