Rethinking Fat: Newly discovered Roles for Fatty Acids in Metabolism

The ability of endothelial cells to proliferate is essential for the growth and creation of new blood vessels throughout the body. While the development of new blood vessels is a completely normal bodily function, when this process becomes out of control diseases such as retinopathy can occur. Fatty acids are important biological molecules that most typically play roles in storing energy for the cell. Previous studies indicated that the majority of the energy produced by endothelial cells during vessel development was from glycolysis. While it is known that fatty acid oxidation is an important energy source for cells under stress in other cell types, the role of fatty acids in the metabolism of endothelial cells remained largely unexplored. CPT1 is an enzyme that catalyzes the rate limiting step of fatty acid oxidation: the transport of fatty acid metabolites into the mitochondria. As such, it was previously believed that disrupting fatty acid oxidation by knocking-down, or silencing, the gene that encodes CPT1 could disrupt catabolic processes in the cell, thereby depleting the cell of a significant source of energy. The authors sought to better understand the role of fatty acid oxidation as a part of the metabolism of endothelial cells during vessel sprouting.

The authors first evaluated the role of fatty acid oxidation in promoting vessel spreading, by performing a CPTL knockdown in human umbilical venous endothelial cells. It was discovered that silencing the enzyme resulted in the reduced proliferation of the cells, but not their motility. The authors then investigated the effect of CPT1 knockdown in vivo in mice pups, and found that the silencing of the enzyme resulted in reduced vessel development in retinal tissue. The reduced proliferation was not due to a reduction in ATP production, nor was there an appreciable difference in oxygen consumption due to the production of ATP, challenging the assumption that fatty acid oxidation was involved in supplying the endothelial cells with energy. In order to evaluate if fatty acids may have been used to construct aspartate and dNTPs, the authors added isotopically-tagged fatty acids to the cells, and discovered that the carbons from these fatty acids was becoming incorporated into aspartate and dNTPs, something that is not typically seen in other cell lines. To check if the reduction of aspartate was effecting protein production the authors evaluated protein production and found no significant difference. To further evaluate the hypothesis, the authors supplemented the cells with dNTPs and additional glucose to make up for the theorized loss of dNTPs from fatty acid oxidation. The authors found that dNTPs were able to rescue sprouting, but that glucose was unable to make up for the loss of fatty acid oxidation, suggesting that fatty acids oxidation may be essential in supplying the cell with dNTPs. Penultimately, the authors added isotopically tagged fatty acids to a variety of cell types and strains and found that most cells do not use fatty acid oxidation to create dNTPs and other such molecules, indicating the novelty of system found in endothelial cells. Finally, the authors found that inhibiting CPT1 resulted in a reduction in angiogenesis similar to the silencing the enzyme, suggesting a possible clinical target.

The discovery that Fatty Acid Oxidation plays a critical role in the production of dNTP precursors was quite surprising. The authors’ work challenges the idea that fatty acid oxidation is solely used for the production of energy in cells, challenging long held ideas about fatty acids’ role in metabolism. Importantly, the authors’ work shed a great deal of light of fatty acid’s role in endothelial cells, a previously unexplored are. More specifically, the authors’ conclusions suggest that targeting CPT1, and other enzymes involved in fatty acid oxidation, can reduce the overproliferation of blood vessels. Thus, they pave the road for new drugs treatments for diseases such as retinopathy.

An overview of endothelial cell metabolism.

 

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