The Undercover Role of Fatty Acids

Endothelial cells line the interior surface of blood and lymphatic vessels and are responsible for the formation of new blood vessels, a process known as angiogenesis. Angiogenesis requires the proliferation and migration of endothelial cells, processes that are most commonly thought to be fueled by the conversion of simple carbon sugars into more complex macromolecules. However, Schoors et al. reports a role of the oxidation of fatty acids into acetyl-CoA as the carbon source needed for macromolecule synthesis, such as the precursors of nucleotides for DNA synthesis, that are necessary for cellular proliferation. The inhibition of fatty acid oxidation (FAO) has clinical implications through the suppression of endothelial cell proliferation. This serves as a mechanistic approach to prevent disorders caused by uncontrolled angiogenesis, as demonstrated in mice by preventing retinopathy, a vision loss disorder caused by rapid and excessive blood vessel formation.

In order to study the role of FAO in endothelial cell proliferation, Schoors et al. silenced carnitine palmitoyltransferase 1 (CPT1) in endothelial cells of mice, the enzyme responsible for shuttling fatty acids into the mitochondria. Once inside, FAO into acetyl-CoA fuels the tricarboxylic acid cycle (TCA), which is responsible for macromolecule synthesis necessary for proliferation. Silencing of CPT1 caused impaired vessel sprouting in endothelial cells and mice retina, demonstrating the prevention of proliferation without affected cellular migration.

To determine the mechanism by which FAO regulates cellular proliferation, it was investigated whether energy production was affected by the silencing of CPT1, since it is known that FAO has a role in energy production. However, the amount of ATP, which is also a product of the TCA, generated was not affected by the lack of CPT1. Furthermore, the absence of CPT1 did not impair protein or RNA levels. Instead, the precursors for deoxyribonucleotide triphosphates (dNTPs) became depleted, suggested that FAO has a specific role in DNA synthesis. This is supported through the addition of dNTPs or acetate, another acetyl-CoA precursor, allowing for cell proliferation by reversing the effects of CPT1 loss. The role of FAO in DNA synthesis was surprising since most proliferating cells do not use fatty acids as a major carbon source. Thus, the role of FAO in carbon fueling the TCA and therefore, allowing for the production of precursors needed for DNA synthesis was unexpected since many cancer types rely on sugar carbon sources.

Furthermore, these findings demonstrate the specificity of FAO involvement in DNA synthesis, demonstrating the ability for this pathway to be targeted without causing the depletion of components of the metabolic pathway, or affecting the ability for the epithelial cells to migrate. In contrast, previous research has demonstrated that glucose metabolism is needed for both cellular proliferation and migration.

The specificity of the FAO metabolic pathway provides a therapeutic potential for diseases caused by atypical proliferation of endothelial cells. This is demonstrated in a mice model to control abnormal angiogenesis causing retinopathy of prematurity, which is a major source of long-term vision function affecting majority of newborn babies with extremely low birth weights worldwide. Perhaps more cell lines will be discovered that use FAO as part of the proliferation pathway, such as in tumor development, in order to treat diseases caused by excessive angiogenesis.

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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