| Literature DB >> 28024299 |
Brian W Wong1,2, Xingwu Wang1,2, Annalisa Zecchin1,2, Bernard Thienpont3,4, Ivo Cornelissen1,2, Joanna Kalucka1,2, Melissa García-Caballero5, Rindert Missiaen1,2, Hongling Huang1,2, Ulrike Brüning1,2, Silvia Blacher5, Stefan Vinckier1,2, Jermaine Goveia1,2, Marlen Knobloch6, Hui Zhao3,4, Cathrin Dierkes7, Chenyan Shi1,2, René Hägerling7, Veronica Moral-Dardé1,2,8, Sabine Wyns1,2, Martin Lippens1,2, Sebastian Jessberger6, Sarah-Maria Fendt9,10, Aernout Luttun11, Agnès Noel5, Friedemann Kiefer7, Bart Ghesquière8, Lieve Moons12, Luc Schoonjans1,2, Mieke Dewerchin1,2, Guy Eelen1,2, Diether Lambrechts3,4, Peter Carmeliet1,2.
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.Entities:
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Year: 2016 PMID： 28024299 DOI： 10.1038/nature21028
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962