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Author: Brendan Trafford

Fatty Acid oxidation is crucial for many pathways and functions in the human body. The product of fatty acid oxidation, Acetyl-CoA, plays many vital roes in energy generation and biosynthesis of larger macromolecules. In the paper by Wong and his associates, they further investigate the role of fatty acid oxidation and Acetyl-CoA in the formation of lymphatic endothelial cells (LEC). This research primarily focuses on the role of CPT-1 (Carnitine palmitoyl-transferase 1) which converts Acetyl-CoA into fatty acyl-carnitine which it can then move from the outer membrane of the mitochondria to the mitochondrial matrix. From here CPT-2 then takes this acyl-carnitine and turn it back into Acetyl CoA where it can generate citrate and other core molecules for the formation of new LEC cells.

The lymphatic system is key in blood transfer and immune health. Lymph angiogenesis (the creation of LECs) is key to a strong and healthy lymphatic system. Mammals produce three forms of CPT1 (CPTa1, CPT1b and CPT1c) but CPT1a is seen in higher concentration of LECs. In previous studies removing this form of CPT1 leads to a steep decrease in the formation of LECs. FOA and further b-oxidation leads to the formation of ATP which can be used to help form LECs. Although this reaction was seen in LECs it was not any higher than any other cells in the body and therefore could not play a direct role in why some cells become LECs or VECs.

Acetyl-CoA made by FAO could help to regulate certain genes that would promote the formation of LECs over VECs. These Acetyl-CoAs that are made could help to Acylate histones and allow certain genes to be expressed more. Acylation of proteins are very sensitive to changes in Acetyl-CoA concentration so having Acetyl-CoA in high concentrations could lead to an increase in histone Acylation. To test this the authors impaired the function of CPT1a and looked how it affected certain genes that lead to the creation of LECs. They found that the impairment of CPT1a lead to an alteration of expression in VEGFR, a LEC Marker, and decreased histone acylation.  To lower CPT1a levels the authors impaired PROX-1 (a protein that induces CPT1a expression and binds p-300 histone acyltransferases to LEC gene to allow differentiation).

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