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The role of fatty acid β-oxidation in lymphangiogenesis

Author

Listed:
  • Brian W. Wong

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Xingwu Wang

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Annalisa Zecchin

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Bernard Thienpont

    (Laboratory of Translational Genetics
    Laboratory of Translational Genetics, VIB Vesalius Research Center)

  • Ivo Cornelissen

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Joanna Kalucka

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Melissa García-Caballero

    (Laboratory of Biology of Tumor and Development, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège)

  • Rindert Missiaen

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Hongling Huang

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Ulrike Brüning

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Silvia Blacher

    (Laboratory of Biology of Tumor and Development, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège)

  • Stefan Vinckier

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Jermaine Goveia

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Marlen Knobloch

    (Brain Research Institute, Faculty of Medicine and Science, University of Zurich)

  • Hui Zhao

    (Laboratory of Translational Genetics
    Laboratory of Translational Genetics, VIB Vesalius Research Center)

  • Cathrin Dierkes

    (Mammalian Cell Signaling Laboratory, Max Planck Institute for Molecular Biomedicine)

  • Chenyan Shi

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • René Hägerling

    (Mammalian Cell Signaling Laboratory, Max Planck Institute for Molecular Biomedicine)

  • Veronica Moral-Dardé

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center
    Metabolomics Core Facility, VIB Vesalius Research Center)

  • Sabine Wyns

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Martin Lippens

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Sebastian Jessberger

    (Brain Research Institute, Faculty of Medicine and Science, University of Zurich)

  • Sarah-Maria Fendt

    (Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Vesalius Research Center
    Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer Institute (LKI))

  • Aernout Luttun

    (Center for Molecular and Vascular Biology, KU Leuven)

  • Agnès Noel

    (Laboratory of Biology of Tumor and Development, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège)

  • Friedemann Kiefer

    (Mammalian Cell Signaling Laboratory, Max Planck Institute for Molecular Biomedicine)

  • Bart Ghesquière

    (Metabolomics Core Facility, VIB Vesalius Research Center)

  • Lieve Moons

    (Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section)

  • Luc Schoonjans

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Mieke Dewerchin

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Guy Eelen

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

  • Diether Lambrechts

    (Laboratory of Translational Genetics
    Laboratory of Translational Genetics, VIB Vesalius Research Center)

  • Peter Carmeliet

    (Laboratory of Angiogenesis and Vascular Metabolism
    Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center)

Abstract

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.

Suggested Citation

  • Brian W. Wong & Xingwu Wang & Annalisa Zecchin & Bernard Thienpont & Ivo Cornelissen & Joanna Kalucka & Melissa García-Caballero & Rindert Missiaen & Hongling Huang & Ulrike Brüning & Silvia Blacher &, 2017. "The role of fatty acid β-oxidation in lymphangiogenesis," Nature, Nature, vol. 542(7639), pages 49-54, February.
    • Handle: RePEc:nat:nature:v:542:y:2017:i:7639:d:10.1038_nature21028
    DOI: 10.1038/nature21028
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    Cited by:

    1. Nieves Montenegro-Navarro & Claudia García-Báez & Melissa García-Caballero, 2023. "Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Odeta Meçe & Diede Houbaert & Maria-Livia Sassano & Tania Durré & Hannelore Maes & Marco Schaaf & Sanket More & Maarten Ganne & Melissa García-Caballero & Mila Borri & Jelle Verhoeven & Madhur Agrawal, 2022. "Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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