The lymphatic system works to regulate tissue homeostasis, collect antigens, and transport immune cells. Lymphangiogenesis takes place primarily during embryogenesis and is rarely seen postnatally, when it occurs in adults it is typically under conditions such as inflammation, tissue repair and tumor growth (Christiansen and Detmar, 2011). In their study, Wong et al. (2016) provide research on a novel pathway involving fatty acid β-oxidation and through which lymphangiogenesis is regulated.
Fatty acid β-oxidation (FAO) is the process by which fatty acids are broken down to produce acetyl co-enzyme A (acetyl-CoA) molecules. The cell can then either keep the molecules for future applications or use them to generate citrate for the citric acid cycle. FAO takes place in the mitochondria, where fatty acids linked to co-enzyme A are brought in by the enzyme carnitine palmitoyltransferase (CPT1). The authors observed this process to be especially prevalent in lymphatic endothelial cells (LECs), which line lymphatic vessels and play important roles in controlling homeostasis, lipid transport and inflammation. They found that by knocking out CPT1 in LEC cells, proliferation and migration was reduced, thus inhibiting lymphatic development.
In order for LECs to differentiate from venous endothelial cells (VECs), two regulatory signals are required: PROX1 and VEGFR3. The authors found that PROX1 serves as a transcription factor for CPT1A with its overexpression increasing transcription of CPT1A. FAO expression is thus enhanced through PROX1 transcription of CPT1A. Previous research indicates that LECs lacking CPT1A have lower VEGF3 levels and that it is regulated by histone acetyltransferase p300. The authors found that PROX1 interacts with histone acetyltransferase p300, possibly regulating VEGFR3 epigenetically. Silencing p300 produced effects similar to those observed when knocking out CPT1A. The ratio of acetyl-CoA to CoA was found to be increased in PROX1 overexpressed cells, relating acetylation by p300 to acetyl-CoA levels. Also, PROX1 overexpression resulted in increased H3K9 levels, which is highly correlated to active promoters. The authors suggest a mechanism through which FAO might provide acetyl-CoA (to increase the acetyl-CoA/CoA ratio) for histone acetylation. They suggest that differentiation of LECs from VECs requires both epigenetic modifications and the generation of acetyl-CoA from fatty acid.
Prior to this research, the metabolic pathways regulating lymphatic development were unknown. PROX1 was understood to work as a transcription factor, binding to the promoter of lymphatic genes and inducing their transcription. Yet, while this is not incorrect, these new findings introduce a novel role to PROX1; not only does it work as a transcription factor for lymphatic genes but it also works epigenetically to boost its own activity. This it does by inducing CPT1A expression, which in turn enhances production of acetyl-CoA, increasing acetylation at lymphatic genes, making it easier for PROX1 to access binding sites. It also interacts directly with p300, recruiting it to PROX1 target genes. Successful differentiation of cells requires both interaction with HAT p300 and CPT1A expression.These findings could be relevant to future therapies looking to treat diseases where dysregulated lymphangiogenesis is an issue.
In a corneal model, where lymphangiogenesis plays an important role in ocular tumor progression and corneal transplant rejection, the authors found that when supplemented with acetate, acetyl-CoA stores was replenished and differentiation defects were recovered: the acetyl-CoA/CoA ratio, H3K9ac levels, and VEGFR3 expression were all rescued (Nakao et al 2012). Additionally, the authors noted that after injecting etomoxir treated mice with acetate, lymphangiogenesis was restored. In the future, further studies could be used to explore similar type mechanisms in other cell types.
Christiansen A and Detmar M. (Dec 2011). Lymphangiogenesis and Cancer. Genes Cancer. 2(12):1146-58
Nakao S, Hafezi-Moghadam A and Ishibashi T. (2012). Lymphatics and Lymphangiogenesis in the Eye. J Ophthalmol. 2012: 783163
Wong et al. (Feb 2017).The role of fatty acid β-oxidation in lymphangiogenesis. Nature. 542: 49-54.
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