Fatty-Acid Oxidation Does What?!

 

Figure 1. FAO pathway highlighting the role of CPT1A and the importance of acetyl-CoA.  Source:http://www.kegg.jp/kegg-bin/show_pathway?ko00071+K08765

A recent study ofangiogenesis, or blood-vessel formation, lead to an important, and surprising discovery concerning the role of fatty-acid oxidation on the proliferation of endothelial cells. Endothelial cells are a type of vascular cells, and during child development the over-proliferation of these cells can lead to retinopathy of prematurity, and eventually, vision loss. In hopes of finding a drug target that can prevent or cure this phenotype, schoors et al performed an analysis of the essential metabolites and process involved in angiogenesis.

Due to its significance, the process of blood-vessel formation has been studied quite thoroughly. As cells divide to create new blood-vessels, energy and DNA precursors are needed. Most other, well-studied, cells metabolize sugars and amino acids to produce energy and dNTPs, respectively. An essential player in both of these pathways is acetyl-CoA. Since energy sources for angiogenesis have been discovered, the Schoors et al article focused on studying the roles and sources of acetyl-CoA in this process.

One of the main sources of acetyl-CoA in a cell is fatty-acid oxidation (FAO), which is the breakdown of long fatty-acid chains into smaller molecules. Each one of these “units” consists of two carbons attached to co-enzyme A, making acetyl-CoA. To understand the role of FAO in blood-vessel formation, Schoors et al knocked down the gene responsible for an important enzyme in FAO, cartinine palmitoltranferase 1A (CPT1A). The CPT1A knock-down exhibited suppressed proliferation of endothelial cells (EC), confirming that FAO plays a major role in the process.

What surprised the authors the most, however, was the nature of the role of FAO in angiogenesis. Before making their discovery, the authors performed many experiments to rule out the logical possibilities for the impaired EC proliferation that they observed. They were able to rule out ATP production and redox imbalance as reasons for impairing the

process. The next step that the authors took was unexpected, and it led to unforeseen findings. They questioned whether FAO played a role in nucleotide synthesis, and surprisingly, the results confirmed their suspicions. It was found that fatty-acid oxidation supplied EC cells with carbons necessary for fueling the TCA cycle, which produces dNTP building blocks such as aspartate.

This is an astonishing new discovery that can possibly lead to the creation of a drug that inhibits FAO in newborns affected with retinopathy of prematurity. The next step, for now, will be to study the role, if any, of FAO in tumor vascularization.

References:
1. Schoors, S. et alNature 520, 192-197 (2005).

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