Lymphangiogenesis is promoted by epigenetic modifications

Author: Brandon Eden

Acetyl CoA is an infamous metabolic player that links many biochemical pathways. It can be formed by the pyruvate dehydrogenase complex after glycolysis and by the process of fatty acid oxidation (FAO). Acetyl CoA also has many metabolic roles such as entry into the citric acid cycle, serving as a precursor for lipid synthesis, and its acetyl group can be used by histone acetyltransferases (HATs) to regulate gene expression. FAO is the cell’s way of creating more acetyl CoA to create energy when the cell requires it, and researchers recently found higher rates of FAO in lymphatic endothelial cells (LEC) than other human endothelial cell types when investigating metabolism in lymphatic development (Wong et al,. 2016).

In order for fatty acids to be metabolized into acetyl CoA, they must enter the mitochondria via the carnitine shuttle. The outer mitochondrial membrane is the site of carnitine palmitoyltransferase I (CPT1), which catalyzes the transformation of fatty acyl CoA to fatty acyl carnitine. Fatty acyl carnitine then enters the mitochondria by traveling through a transporter in the inner mitochondrial membrane, and then it is converted back to fatty acyl CoA by carnitine palmitoyltransferase II (CPTII). The fatty acyl CoA can then undergo a series of oxidations, resulting in the two-carbon product, acetyl CoA, each round.

Lymphatic vessels are formed through lymphangiogenesis, and the vessels are composed of LECs that differentiated from venous endothelial cells (VEC). Proper cell differentiation is required for the lymphatic system to successfully carry out its roles in the body such as absorbing excess fluid to redirect to the circulatory system and aid in mounting immune responses. The significant amount of FAO occurring in LEC was linked to increased expression of the CPT1A isoform of CPT1 in LECs (Wong et al,.).  Thus, Wong et al. hypothesized that CPT1A promotes lymphangiogenesis.

Levels of FAO were shown to respond to lymphangiogenic signals that promote VEC-to-LEC differentiation. The authors overexpressed PROX1 in vitro, a transcription factor, and this resulted in an increase in CPT1A mRNA and FAO levels that was similar to those observed in LECs (Wong et al,.). Similarly, silencing PROX1 resulted in lower levels of FAO and CPT1A (Wong et al,.). Levels of FAO and CPT1A were then linked to LEC differentiation when CPT1A knockdown mice displayed reduced LEC proliferation marked by low levels of VEGFR3, which results in lymphatic defects (Wong et al,.). PROX1 induces CPT1A expression which increases FAO, and the resulting acetyl CoA molecules can help deoxyribonucleotide synthesis, but this is not directly linked to LEC differentiation. The authors then hypothesized that acetyl CoA could play an epigenetic role that increases the expression of lymphangiogenic genes (Wong et al,.).

Co-immunoprecipitation experiments showed that a well-known histone acetyltransferase, p300, interacts with PROX1 (Wong et al,.). This histone acetyltransferase was found to acetylate histone H3 at lysine 9, loosening the interaction between DNA and the histone, allowing PROX1 to bind the promotor sequence and stimulate lymphangiogenic gene expression (Wong et al,.). Acetyl CoA levels were also shown to depend on histone acetylation by p300 (Wong et al,.). Lymphangiogensis is dependent on this epigenetic modification, and when acetyl CoA is absent, the authors have demonstrated that supplementing with acetate can restore lymphangiogenesis by serving as an acetyl donor that p300 can use to stimulate lymphangiogenic gene expression (Wong et al,.). The findings of Wong et al,. can be translated in the clinic, and further studies of the many fates of acetyl CoA should be conducted. The importance of acetyl CoA cannot be emphasized enough, and its many fates are still being discovered. These pathways need to be elucidated to understand healthy physiology in addition to disease pathology.

 

Reference:

Wong, B.W., Wang, X., Zecchin, A., Thienpont, B., Cornelissen, I., Kalucka, J., Garcia-Caballero, M., Missiaen, R., Huang, H., Bruning, U., et al. (2016). Nature. http://dx.doi.org/10.1038/nature21028.

 

 

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