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

Nature. 2017 Feb 2;542(7639):49-54. doi: 10.1038/nature21028. Epub 2016 Dec 26.

Authors

Brian W Wong^{1

2}, Xingwu Wang^{1

2}, Annalisa Zecchin^{1

2}, Bernard Thienpont^{3

4}, Ivo Cornelissen^{1

2}, Joanna Kalucka^{1

2}, Melissa García-Caballero⁵, Rindert Missiaen^{1

2}, Hongling Huang^{1

2}, Ulrike Brüning^{1

2}, Silvia Blacher⁵, Stefan Vinckier^{1

2}, Jermaine Goveia^{1

2}, Marlen Knobloch⁶, Hui Zhao^{3

4}, Cathrin Dierkes⁷, Chenyan Shi^{1

2}, René Hägerling⁷, Veronica Moral-Dardé^{1

2

8}, Sabine Wyns^{1

2}, Martin Lippens^{1

2}, Sebastian Jessberger⁶, Sarah-Maria Fendt^{9

10}, Aernout Luttun¹¹, Agnès Noel⁵, Friedemann Kiefer⁷, Bart Ghesquière⁸, Lieve Moons¹², Luc Schoonjans^{1

2}, Mieke Dewerchin^{1

2}, Guy Eelen^{1

2}, Diether Lambrechts^{3

4}, Peter Carmeliet^{1

2}

Affiliations

¹ Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.
² Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
³ Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.
⁴ Laboratory of Translational Genetics, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
⁵ Laboratory of Biology of Tumor and Development, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer (GIGA-Cancer), University of Liège, Liège B-4000, Belgium.
⁶ Brain Research Institute, Faculty of Medicine and Science, University of Zurich, Zurich 8057, Switzerland.
⁷ Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster 48161, Germany.
⁸ Metabolomics Core Facility, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
⁹ Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Vesalius Research Center, VIB, B-3000 Leuven, Belgium.
¹⁰ Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), B-3000 Leuven, Belgium.
¹¹ Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven B-3000, Belgium.
¹² Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Leuven B-3000, Belgium.

PMID: 28024299
DOI: 10.1038/nature21028

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetates / pharmacology
Acetyl Coenzyme A / metabolism
Acetylation / drug effects
Animals
Carnitine O-Palmitoyltransferase / antagonists & inhibitors
Carnitine O-Palmitoyltransferase / genetics
Carnitine O-Palmitoyltransferase / metabolism
Cell Differentiation / drug effects
Cell Differentiation / genetics
Endothelial Cells / cytology
Endothelial Cells / drug effects
Endothelial Cells / metabolism
Epigenesis, Genetic
Fatty Acids / chemistry*
Fatty Acids / metabolism*
Female
Histones / metabolism
Homeodomain Proteins / metabolism
Human Umbilical Vein Endothelial Cells
Humans
Lymphangiogenesis* / drug effects
Lymphangiogenesis* / genetics
Lymphatic Vessels / cytology*
Lymphatic Vessels / drug effects
Lymphatic Vessels / metabolism*
Mice
Mice, Inbred C57BL
Oxidation-Reduction / drug effects
Protein Biosynthesis
Transcription, Genetic
Tumor Suppressor Proteins / metabolism
Umbilical Arteries / cytology
Up-Regulation

Substances

Acetates
Fatty Acids
Histones
Homeodomain Proteins
Tumor Suppressor Proteins
prospero-related homeobox 1 protein
Acetyl Coenzyme A
CPT1B protein, mouse
Carnitine O-Palmitoyltransferase