Fatty acid beta-oxidation (FAO) is an instrumental process in metabolism. This process begins by transportation of the fatty acyl-CoA molecules into the mitochondria. Carnitine palmitoyl-transferase 1 (CPT1) replaces the acetyl-CoA group with a carnitine group, and the fatty acid carnitine is able to use a transport protein the cross the membrane. After crossing, a similar transferase enzyme replaces the carnitine group with acetyl-CoA. This process separates the metabolic pools of fatty-acyl CoA and serves as a regulatory step in FAO. These fatty-acyl CoAs are then broken down in a four-step process to yield surprising amounts of energy. Arguably more importantly, however, is the production of acetyl-CoA, the quintessential metabolic intermediate. Acetyl-CoA plays many roles in metabolism, but is often utilized in the citric acid cycle to generate ATP.
Wong et. al. (2016) discusses one of the pathways in which this acetyl-CoA is not utilized for cellular energetics. Lymphatic endothelial cells (LEC)s differentiate from venous endothelial cells with the help of transcriptional factors such as VEGF-C. After differentiation, these cells can form the lymphatic system, which plays key roles in homeostatic functions for an organism. Significant disruption of this system is often lethal.
After noticing that in LECs, rates of FAO were much higher and rates of glycolytic activity were lower, the group became suspicious of this increased rate of FAO. Eliminating FAO resulted in little change to the cellular energetics, implying the cells have some level of metabolic flexibility. Such large amount of FAO may not simply be to create energy for the cell. It was discovered that the acetyl-CoA produced via this process was being utilized by a histone acetyltransferase (HAT) to epigenetically regulate lymphangiogenesis. The HAT enzyme functions by acetylating a lysine residue on the tail end of a specific histone, allowing the DNA to be more readily accessed and transcribed.
Furthermore, knocking out one of the prevalent isozymes of CPT-1, CPT1-A, resulted in a failure to differentiate from the venous endothelial cell stage to the LEC stage. The loss of functional CPT-1A resulted in a complete halt to FAO. A lack of histone deacetylation was observed, leading Wong et. al. to conclude that FAO is essential in creating the amount of acetyl-CoA necessary to illicit this epigenetic change. Furthermore, supplementing these altered cells with acetate successfully ‘rescued’ them, allowing the necessary epigenetic changes to occur.
This newfound dependency of cell-differentiation on acetyl-CoA produced by FAO is fascinating. It’s possible other physiological processes are dependent on the classic metabolic intermediate, or other intermediates, and we’ve simply overlooked them. A better understanding of the ways in which metabolism regulates both itself and other physiological processes, such as epigenetics, will be crucial in furthering our understanding of complex disease pathologies and how to treat them. Future work will inevitably investigate whether similar paths of epigenetic regulation via metabolism exist.
Wong et. al. build upon the traditional model of PROX1 functionality, proving that the transcription factor not only promotes the transcription of LEC genes, but also promotes FAO acetyl-CoA production to make epigenetic changes and further increase its efficacy as a transcription factor. This approach serves to significantly change their understanding of the mechanisms at play in this system while holding valid their previous research. The sheer multitude of evidence presented in this paper tells a story; this high-impact research, accessible by many readers of many different disciplines, may redefine the way we see epigenetic modification in tandem with metabolism. The overwhelming volume of such a paper, however, needs to be distilled into a more readily digestible form, and that is what this post has attempted to accomplish. Β-oxidation, it seems, is complicated…
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