“The role of fatty acid β-oxidation in lymphangiogenesis” Spotlight

Acetyl CoA has many different roles in various pathways, serving in making energy, biosynthesis, and in post-transnational modifications controlling epigenetic gene expression. Wong et al. covers the role of fatty acid beta-oxidation in lymphatic endothelial cells (LECs) in generating Acetyl CoA for the purpose of acetylating histones in lymphangiogenesis.  Carnitine palmitoyl-transferase 1 (CPT1) converts acyl CoA into fatty acyl-carnitine and fatty acyl CoA gets regenerated by CPT2. Beta-oxidation converts fatty acyl CoA into acetyl CoA. Acetyl CoA combines with ocalacetate to make citrate which then regenerates acetyl-CoA. Acetyl-CoA then can act as a substrate for acetylation reactions.

Lymphatic endothelial cells must differentiate from venous endothelial cells, and when the forming of lymphatic vessels can’t occur, it can have the ability to cause various diseases, including cancer and lymphedema. Wong et al. hypothesized that CPT1A is critical in LECs for lymphangiogenesis, which was correct, and suggests that the transportation of lipids across mitochondrial membranes is necessary.

Wong et al. did not see any alterations when FAO was blocked in endothelial cells, but the cell may have other ways to make up for production of ATP from the source of fatty acids. FAO may also play a role in membrane turnover during lymphangiogenesis because acetyl-CoA can provide two carbons for biosynthesis and is the substrate of fatty acid synthesis. FAO can enable nucleotide biosynthesis, which means there may be a link with the TCA cycle.

Acetyl-CoA’s availability from FAO can play a role in protein function by its activity in acetylation and also can acetylate histones to regulate gene expression. Acetylated histone lysine residues de-represses transcription of close genes.

Wong et al. found that acetyl CoA from FAO is indeed important for regulation of epigenetics pertaining to lymphangiogenesis. They also found that expression of LEC markers is altered and histone acetylation is decreased when CPT1A is lost. Prox1 binds p300 histone acetyltransferase to enhance acetylation of LEC genes, which allows them to be differentiated from others. Prox1 is important because it induces CPT1A expression. In order for LEC cells to be differentiated, histones must be acetylated and fatty acid stores must be mobilized to make acetyl-CoA. Acetate can reverse the inhibition of CPT1A and save lymphangiogenesis, as well.

Wong et al. concludes that the growth and differentiation of endothelial cells greatly relies on FAO. It is possible that other cells that differentiate may be dependent on acetyl-CoA, as well. As mentioned above, acetyl-CoA may be important in cancer. Acetate can disrupt the ability to make acetyl-CoA which has the ability to impair cell proliferation and is important to cell energetics.

Future work can include extended work with acetyl-CoA and what other mechanisms are dependent on it, in LECs or other cell types. A better understanding of metabolism and development in different tissues can be explored.  This can give better insight into normal versus diseased cells and their makeup.

http://www.nature.com.muhlenberg.idm.oclc.org/articles/nature21028

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