Author: ["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","Peter Carmeliet"]
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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. The lymphangiogenic factor PROX1 transcriptionally upregulates CPT1A, a rate-controlling enzyme in fatty acid β-oxidation, and this co-regulates lymphatic endothelial cell differentiation by epigenetic control of lymphatic gene expression, demonstrating a role for metabolism in developmental biology. Peter Carmeliet and colleagues demonstrate a role for metabolism in the differentiation of lymphatic endothelial cells. They report that the lymphangiogenic factor PROX1 transcriptionally upregulates the enzyme CPT1A, a rate-limiting step in fatty acid β-oxidation, and that fatty acid β-oxidation regulates lymphatic endothelial-cell differentiation by the epigenetic control of lymphatic genes. Inhibiting fatty acid β-oxidation can rescue pathological lymphangiogenesis.Cite this article
Wong, B., Wang, X., Zecchin, A. et al. The role of fatty acid β-oxidation in lymphangiogenesis. Nature 542, 49–54 (2017). https://doi.org/10.1038/nature21028 