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.

Benzene induces haematotoxicity by promoting deacetylation and autophagy

“…Further works should be proceeded to clarify the mechanism how HQ decrease the expression of p300 at the transcriptional level in future studies. As we all know, activity of p300 depends on the concentration of acetyl‐CoA and meanwhile, acetyl‐CoA is also mostly regulated by p300 . So HQ deregulated this cycle and resulted in autophagy and eventually cell death.…”

Lymphatic Vessel Network Structure and Physiology

“…Mechanistically, Prox1 directly upregulates CPT1A expression, which increases acetyl coenzyme A production. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes, such as Vegfr3 to regulate LEC migration and identity maintenance (1152). …”

The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity

“…These data suggest that CD36 enhances adipose tissue inflammation and cell death in diet-induced obesity through its expression in adipocytes and macrophages and that a CD36-dependent inflammatory paracrine loop between adipocytes and macrophages ease chronic inflammation and cooperate to insulin resistance in obesity (Kennedy et al, 2011). Furthermore, considering that CD36 is a fatty acid translocase expressed in endothelial cells, and that LECs use fatty acid β-oxidation to proliferate (Wong et al, 2017), it is tempting to speculate that loss of CD36 might affect the fuel supply needed for LECs maintenance, and ultimately their proliferation and migration.…”