The role of fatty acid β-oxidation in lymphangiogenesis

Brian W. Wong, Xingwu Wang, Annalisa Zecchin, Bernard Thienpont, Ivo Cornelissen, Joanna Kalucka, Melissa García-Caballero, Rindert Missiaen, Hongling Huang, Ulrike Brüning, Silvia Blacher, Stefan Vinckier, Jermaine Goveia, Marlen Knobloch, Hui Zhao, Cathrin Dierkes, Chenyan Shi, René Hägerling, Veronica Moral-Dardé, Sabine Wyns, Martin Lippens, Sebastian Jessberger, Sarah-Maria Fendt, Aernout Luttun, Agnès Noel, Friedemann Kiefer, Bart Ghesquière, Lieve Moons, Luc Schoonjans, Mieke Dewerchin, Guy Eelen, Diether Lambrechts and Peter Carmeliet ()
Additional contact information
Brian W. Wong: Laboratory of Angiogenesis and Vascular Metabolism
Xingwu Wang: Laboratory of Angiogenesis and Vascular Metabolism
Annalisa Zecchin: Laboratory of Angiogenesis and Vascular Metabolism
Bernard Thienpont: Laboratory of Translational Genetics
Ivo Cornelissen: Laboratory of Angiogenesis and Vascular Metabolism
Joanna Kalucka: Laboratory of Angiogenesis and Vascular Metabolism
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
Hongling Huang: Laboratory of Angiogenesis and Vascular Metabolism
Ulrike Brüning: Laboratory of Angiogenesis and Vascular Metabolism
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
Jermaine Goveia: Laboratory of Angiogenesis and Vascular Metabolism
Marlen Knobloch: Brain Research Institute, Faculty of Medicine and Science, University of Zurich
Hui Zhao: Laboratory of Translational Genetics
Cathrin Dierkes: Mammalian Cell Signaling Laboratory, Max Planck Institute for Molecular Biomedicine
Chenyan Shi: Laboratory of Angiogenesis and Vascular Metabolism
René Hägerling: Mammalian Cell Signaling Laboratory, Max Planck Institute for Molecular Biomedicine
Veronica Moral-Dardé: Laboratory of Angiogenesis and Vascular Metabolism
Sabine Wyns: Laboratory of Angiogenesis and Vascular Metabolism
Martin Lippens: Laboratory of Angiogenesis and Vascular Metabolism
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
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
Mieke Dewerchin: Laboratory of Angiogenesis and Vascular Metabolism
Guy Eelen: Laboratory of Angiogenesis and Vascular Metabolism
Diether Lambrechts: Laboratory of Translational Genetics
Peter Carmeliet: Laboratory of Angiogenesis and Vascular Metabolism

Nature, 2017, vol. 542, issue 7639, 49-54

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature21028

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