The role of fatty acid β-oxidation in lymphangiogenesis

Acetyl-CoA has long been known for its importance as a metabolic intermediate for many pathways. For example, this intermediate can be used in anabolic pathways as in the case for fatty-acid synthesis in the cytosol of human cells, or could be a product of catabolic pathways like fatty-acid oxidation in the mitochondria. Most recently however, acetyl-CoA has been shown to be involved in other functions in the body, particularly with respect to the formation of lymphatic vessels and the process of lymphangiogenesis. In their recent publication in Nature, Wong et al. explain how lymphatic endothelial cells (LECs) use fatty-acid beta-oxidation (FAO) for differentiation and epigenetic regulation through histone acylation (Wong et al., 2016).

In order for FAO to occur, acetyl-CoA must first be transported from the vicinity of the cytosol across the mitochondrial membrane and into the mitochondrial matrix in the form of fatty-acyl CoA. This is done through the mechanism of the enzyme carnitine palmitoyl-transferase 1 (CPT1), which is the rate-limiting step for FAO. Wong et al. devoted their attention to this process in LECs, in which extracellular cues such as VEGF-C promote differentiation of these cells from venous endothelial cells (VECs). The importance of these cells lies in their contribution to normal physiology, as dysregulation can lead to many diseases that include cancer metastasis, organ transplant rejection, and lymphedema (Choi et al., 2012).

Wong et al. initiated their experiment by observing the expression levels of CPT1A in LECs vs. VECs, and found that these levels were higher in the former. This suggested that FAO was also higher in these cells, which led the authors to hypothesize that CPT1A may be directly required for lymphangiogenesis (Wong et al., 2016). This hypothesis was also supported when they performed CPT1A knockdown (CPT1AKD) in LECs, and observed reduced LEC proliferation and migration which led to lymphatic defects in vivo.

Beta-oxidation of fatty acids leads to the production of ATP; however, the authors noticed that CPT1AKD did not cause energy distress. Instead, fatty acids provided acetyl-CoA, which helped to sustain the Krebs cycle and deoxyribonucleotide (dNTP) synthesis for proliferation of LECs. As a result, the authors explored the possibility that acetyl-CoA generated by FAO in LECs might be involved in epigenetic modification of lymphangiogenic gene expression. They focused particularly on VEGFR3 transcription regulated by histone acetyltransferase (HAT) p300 through PROX1. Through their experiments, the authors observed that PROX1 does indeed bind p300 histone acetyltransferase to enhance H3K9 acetylation of LEC genes, which ultimately enables LEC differentiation. Furthermore, they observed that CPT1AKD reduced H3K9ac levels in pLECs to the levels seen in VECs, which supports that histone acylation is directly involved in the successful differentiation of LECs (Wong et al., 2016).

Finally, the authors also display a translational potential for their findings. They found that pharmacological blockade of CPT1 inhibits injury-induced lymphangiogenesis, and that replenishment with acetone actually rescues the defects due to FAO inhibition (Wong et al., 2016). As a result, these findings become of tremendous high impact considering the wide array of potential applications they can lead to, especially with respect to curing dangerous diseases and promoting lymphangiogenesis in pathological conditions such as lymphedema.

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