Role and therapeutic potential of dietary ketone bodies in lymph vessel growth

Nature Metabolism
Melissa García-CaballeroPeter Carmeliet

Abstract

Lymphatic vessels (LVs), lined by lymphatic endothelial cells (LECs), are indispensable for life1. However, the role of metabolism in LECs has been incompletely elucidated. In the present study, it is reported that LEC-specific loss of OXCT1, a key enzyme of ketone body oxidation2, reduces LEC proliferation, migration and vessel sprouting in vitro and impairs lymphangiogenesis in development and disease in Prox1ΔOXCT1 mice. Mechanistically, OXCT1 silencing lowers acetyl-CoA levels, tricarboxylic acid cycle metabolite pools, and nucleotide precursor and deoxynucleotide triphosphate levels required for LEC proliferation. Ketone body supplementation to LECs induces the opposite effects. Notably, elevation of lymph ketone body levels by a high-fat, low-carbohydrate ketogenic diet or by administration of the ketone body β-hydroxybutyrate increases lymphangiogenesis after corneal injury and myocardial infarction. Intriguingly, in a mouse model of microsurgical ablation of LVs in the tail, which repeats features of acquired lymphoedema in humans, the ketogenic diet improves LV function and growth, reduces infiltration of anti-lymphangiogenic immune cells and decreases oedema, suggesting a novel dietary therapeutic opportunity.

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Citations

Jul 23, 2020·Nature Metabolism·Kim D FalkenbergPeter Carmeliet
Jul 23, 2020·Nature Metabolism·Patrycja Puchalska, Peter A Crawford
Jun 2, 2020·Frontiers in Physiology·Pieter R Norden, Tsutomu Kume
Aug 25, 2020·Circulation Research·Guy EelenPeter Carmeliet
Oct 28, 2020·Lymphatic Research and Biology·Francine Blei
Sep 11, 2020·Nature Reviews. Genetics·Ziwei DaiJason W Locasale
Nov 12, 2020·JAMA Network Open·Jennifer Yin Yee KwanFei-Fei Liu
Mar 27, 2021·Nature Reviews. Nephrology·Sébastien J DumasPeter Carmeliet
Apr 9, 2020·Cell Metabolism·Katerina RohlenovaPeter Carmeliet
Nov 14, 2020·The European Respiratory Journal·Mathias DeclercqPeter Witters
Jun 2, 2021·Angiogenesis·Alessandra PasutPeter Carmeliet
Oct 12, 2021·Annual Review of Nutrition·Patrycja Puchalska, Peter A Crawford

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Methods Mentioned

BETA
histone acetylation
acetylation
biopsies
PCR
FACS
electrophoresis
genotyping
dissection

Software Mentioned

NIH
NIH ImageJ
ImageJ
Xcalibur
Prism
Leica MM AF

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