The role of fatty acid beta-oxidation in lymphangiogenesis.

[en] 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 beta-oxidation, impairs lymphatic development. LECs use fatty acid beta-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 beta-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.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Wong, Brian W.

Wang, Xingwu

Zecchin, Annalisa

Thienpont, Bernard

Cornelissen, Ivo

Kalucka, Joanna

Garcia-Caballero, Melissa

Missiaen, Rindert

Huang, Hongling

Bruning, Ulrike

More authors (23 more)

Language :

English

Title :

The role of fatty acid beta-oxidation in lymphangiogenesis.

Publication date :

2017

Journal title :

Nature

ISSN :

0028-0836

eISSN :

1476-4687

Publisher :

Nature Publishing Group, Basingstoke, United Kingdom

Volume :

542

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 17 January 2017

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Scopus citations^®

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212

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