A recent study has revealed a surprising, significant finding on the role of fatty acid oxidation in endothelial cells. Endothelial cells are required for angiogenesis, or the formation of blood vessels. This process has many clinical implications for diseases like cancer and particularly for developmental issues during early life stages in which growth is very extensive. The paper begins with a description of the role of fatty acid oxidation in blood vessel formation. Proliferation and migration of endothelial cells are necessary for blood vessel growth, and the study notes that fatty acid oxidation’s major effect is on proliferation. Without cell proliferation, blood vessels clearly cannot form which can be a preventative process for certain diseases or have a detrimental defect. The greatest area of focus in this study is on carnitine palmitoyltransferase 1 (CPT1) which is an enzyme involved in the rate limiting step of fatty acid oxidation. Human endothelial cells are rich in the isoform CPT1A, so the researchers silenced this enzyme in these cells and studied the effects.
The result of this silencing was that endothelial cells were not proliferating as they typically would. Proliferation decreased in knockdown cells in which fatty acid oxidation was being thwarted. The researchers then considered multiple feasible options as to why endothelial cell proliferation increased in these CPT1Akd cells. From an energetics standpoint, it was discovered that proliferation was not impacted by a lack of ATP in the cells as a result of the enzyme silencing. The knockdowns also did not have a high level of toxicity from reactive oxygen species due to the lack of fatty acid oxidation. What follows these results is a high impact discovery.
The carbons from fatty acid oxidation in endothelial cells are largely used for the synthesis of deoxynucleoside triphosphates. These dNTPs are then used for DNA synthesis and cell proliferation. Thus, if the concentration of dNTPs inside the cell suffers from a large decrease, cell proliferation will obviously also be affected. In most cells, as the authors point out, carbons from glucose and glutamine are what feed into the citric acid cycle. Intermediates from this cycle often end up being incorporated into DNA, so it is surprising that these endothelial cells so highly depend on fatty acid oxidation as a carbon source as opposed to what most other cells use. The authors describe that this can have major clinical implications for a way of inhibiting pathological angiogenesis. Even for inexperienced readers, this paper does demonstrate the high significance of the findings.
References:
Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192-197 (2015).
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