Fatty acid oxidation (FAO) is a process that takes place all over the body which turns fatty acids into energy by breaking down the long chains of carbon present in their structure. This process takes multiple steps to complete and relies on many different enzymes and transport mechanisms along the way. The first step of this process is the get the fatty acids into the mitochondrial matrix. This is done by taking fatty acids that are currently linked to co-enzyme A (fatty acyl-CoA) and detaching the co-enzyme A and attaching it instead to carnitine. This is done by the enzyme carnitine palmitoyl-transferase 1 (CPT1) which is located in the mitochondrial membrane. After it enters the mitochondrial matrix via transport proteins, CPT2 reverts the molecules back to fatty acyl-CoA. Once this process is completed, the fatty acyl-CoA molecules undergo β-oxidation to produce acetyl-CoA molecules. These are then converted into citrate which can either enter the Krebs cycle to produce ATP or be converted back into acetyl-CoA in the cytosol to be used a substrate for acetylation. In this paper, Wong et al describe the integral role FAO has in endothelial cells due to its production of acetyl-CoA which can then be used for histone acetylation, a process necessary for activating the genes involved in lymphangiogenesis (Wong et al., 2016).
The lymphatic system has many important functions in the body such as adaptive immune function, clearing of interstitial fluid, and absorption of dietary lipids. During normal development, there exists extracellular cues to induce differentiation of lymphatic endothelial cells (LECs), which line lymphatic vessels, from venous endothelial cells (VECs) which line blood vessels. When regulation goes wrong this can cause various issues, a notable one being cancer. What Wong et al theorized in this paper is that CPT1A, one of the three isoforms of CPT1 found in mammals, plays a crucial role in lymphangiogenesis due its increased expression in LECs coupled with elevated FAO. Disrupting CPT1A function in a cell halts lymphangiogenesis, thus providing strong evidence that there is a link between it and FAO. Additionally, FAO has been shown to be linked with nucleotide biosynthesis in endothelial cells, suggesting it or its byproducts may be linked to transcription and translation (Schoors et al 2015).
As previously mentioned, acetyl-CoA is produced by FAO. This molecule can then go on in the cell to be a part of numerous types of acetylation reactions. One of these reactions is histone acetylation. What this process accomplishes is neutralizing the positive charge of various lysine residues in the histone protein which allows increased transcription of nearby genes. What Wong et al discover in their experiment is that epigenetic regulation associated with this process of lymphangiogenesis is influenced by the availability of acetyl-CoA produced by FAO. When the authors disabled CPT1A function, they discovered a decrease in histone acetylation and thus a decrease in expression of LEC differentiation markers. This effect was also seen when proteins necessary for exporting acetyl-CoA from inside the mitochondria were disabled. To help definitively show that it was the lack of necessary acetyl groups causing the decreased expression of markers, they demonstrated that addition of exogenous acetate was able to rescue the defect and lymphangiogenesis could occur.
Based on what Wong et al have uncovered in this experiment, it seems only natural to think that differentiation pathways in other parts of the body are also reliant on catabolic mechanisms and their products and/or byproducts. Additionally, though Wong et al show that acetyl-CoA produced via FAO is integral to lymphangiogenesis, the necessity of both acetyl-CoA and FAO beyond this stage of development is unknown. It is known that acetyl-CoA is used in other biosynthetic pathways as well, so exploring its role in the proliferation of other cell types could be a promising area of future study, especially given the nature of cancer as a disease of unchecked proliferation. Further research into the role of acetyl-CoA and related metabolites in cell development would allow us to understand more about what goes on in cells during both normal and diseased states.
Go to Source
Click the link above to make comments on the author’s site
Powered by WPeMatico