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; Peter Carmeliet

doi:10.1038/nature21028

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 WynsMartin 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

Research output: Contribution to journal › Article › peer-review

243 Scopus citations

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.

Original language	English
Pages (from-to)	49-54
Number of pages	6
Journal	Nature
Volume	542
Issue number	7639
DOIs	https://doi.org/10.1038/nature21028
State	Published - Feb 2 2017

Access to Document

10.1038/nature21028

Cite this

Wong, B. W., Wang, X., Zecchin, A., Thienpont, B., Cornelissen, I., Kalucka, J., García-Caballero, M., Missiaen, R., Huang, H., Brüning, U., Blacher, S., Vinckier, S., Goveia, J., Knobloch, M., Zhao, H., Dierkes, C., Shi, C., Hägerling, R., Moral-Dardé, V., ... Carmeliet, P. (2017). The role of fatty acid β-oxidation in lymphangiogenesis. Nature, 542(7639), 49-54. https://doi.org/10.1038/nature21028

@article{7eb2ba448d7a45f18cfdb882381ade6e,

title = "The role of fatty acid β-oxidation in lymphangiogenesis",

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.",

author = "Wong, {Brian W.} and Xingwu Wang and Annalisa Zecchin and Bernard Thienpont and Ivo Cornelissen and Joanna Kalucka and Melissa Garc{\'i}a-Caballero and Rindert Missiaen and Hongling Huang and Ulrike Br{\"u}ning and Silvia Blacher and Stefan Vinckier and Jermaine Goveia and Marlen Knobloch and Hui Zhao and Cathrin Dierkes and Chenyan Shi and Ren{\'e} H{\"a}gerling and Veronica Moral-Dard{\'e} and Sabine Wyns and Martin Lippens and Sebastian Jessberger and Fendt, {Sarah Maria} and Aernout Luttun and Agn{\`e}s Noel and Friedemann Kiefer and Bart Ghesqui{\`e}re and Lieve Moons and Luc Schoonjans and Mieke Dewerchin and Guy Eelen and Diether Lambrechts and Peter Carmeliet",

year = "2017",

month = feb,

day = "2",

doi = "10.1038/nature21028",

language = "English",

volume = "542",

pages = "49--54",

journal = "Nature",

issn = "0028-0836",

number = "7639",

}

Wong, BW, Wang, X, Zecchin, A, Thienpont, B, Cornelissen, I, Kalucka, J, García-Caballero, M, Missiaen, R, Huang, H, Brüning, U, Blacher, S, Vinckier, S, Goveia, J, Knobloch, M, Zhao, H, Dierkes, C, Shi, C, Hägerling, R, Moral-Dardé, V, Wyns, S, Lippens, M, Jessberger, S, Fendt, SM, Luttun, A, Noel, A, Kiefer, F, Ghesquière, B, Moons, L, Schoonjans, L, Dewerchin, M, Eelen, G, Lambrechts, D & Carmeliet, P 2017, 'The role of fatty acid β-oxidation in lymphangiogenesis', Nature, vol. 542, no. 7639, pp. 49-54. https://doi.org/10.1038/nature21028

TY - JOUR

T1 - The role of fatty acid β-oxidation in lymphangiogenesis

AU - Wong, Brian W.

AU - Wang, Xingwu

AU - Zecchin, Annalisa

AU - Thienpont, Bernard

AU - Cornelissen, Ivo

AU - Kalucka, Joanna

AU - García-Caballero, Melissa

AU - Missiaen, Rindert

AU - Huang, Hongling

AU - Brüning, Ulrike

AU - Blacher, Silvia

AU - Vinckier, Stefan

AU - Goveia, Jermaine

AU - Knobloch, Marlen

AU - Zhao, Hui

AU - Dierkes, Cathrin

AU - Shi, Chenyan

AU - Hägerling, René

AU - Moral-Dardé, Veronica

AU - Wyns, Sabine

AU - Lippens, Martin

AU - Jessberger, Sebastian

AU - Fendt, Sarah Maria

AU - Luttun, Aernout

AU - Noel, Agnès

AU - Kiefer, Friedemann

AU - Ghesquière, Bart

AU - Moons, Lieve

AU - Schoonjans, Luc

AU - Dewerchin, Mieke

AU - Eelen, Guy

AU - Lambrechts, Diether

AU - Carmeliet, Peter

PY - 2017/2/2

Y1 - 2017/2/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85016143129&partnerID=8YFLogxK

U2 - 10.1038/nature21028

DO - 10.1038/nature21028

M3 - Article

C2 - 28024299

AN - SCOPUS:85016143129

SN - 0028-0836

VL - 542

SP - 49

EP - 54

JO - Nature

JF - Nature

IS - 7639

ER -

The role of fatty acid β-oxidation in lymphangiogenesis

Abstract

Access to Document

Other files and links

Fingerprint

Cite this