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

The role of fatty acid β-oxidation in lymphangiogenesis.

Author information

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.

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.

PMID:
28024299
DOI:
10.1038/nature21028
[Indexed for MEDLINE]

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