The role of Acetyl-CoA from Fatty Acid β-Oxidation on Lymphangiogenesis
The proper expression of lymphatic endothelial cells and lymphatic vessels is essential for normal physiological function. The role of acetyl-CoA for proper lymphangiogenesis has recently been discovered by Wong et. al in a recent work published by Nature. In “The role of fatty acid β-oxidation in lymphangiogenesis,” they reported the roles of PROX1 and CPT1A in fatty acid β-oxidation (FAO), the metabolic process in which acetyl-CoA is produced as an intermediate. Normal production of acetyl-CoA is essential for proper histone acetylation required for lymphangiogenesis.
PROX1 is a transcriptional factor that is critical for the development of venous endothelial cells (VEC) into lymphatic endothelial cells (LEC), while VEGF-C-VEGFR3 signals regulate these processes. In addition, PROX1 upregulates CPT1A expression, while CPT1A increases acetyl-CoA production during FAO. CPT1A transports a fatty acyl-CoA intermediate into the mitochondrial matrix at which point the intermediate is converted into fatty acyl-CoA. The work conducted by Wong et. al discovered the role of lymphangiogenesis on normal lymphatic vessel formation and that dysregulated lymphangiogenesis can result in diseases, such as cancer metastasis.
Wong et. al began their experiments by comparing metabolic rates in LECs and VECs and found that FAO events and CPT1A expression were greater in LECs than in VECs. Furthermore, in order to unveil whether lymphangiogenesis was dependent on FAO, the authors induced the differential expression of PROX1, which resultantly caused an increase in CPT1A and FAO levels for genes that were overexpressed and conversely, a decrease in genes that were under-expressed. Due to decreased levels of CPT1A, abnormal LEC differentiation and abnormal vessel morphologies occurred. Through this data, Wong et. al were able to conclude that the dysmorphic features were due to improper LEC development as a result of lowered FAO events by way of PROX1 under-expression.
To further understand the effects of FAO on lymphangiogenesis, the authors applied a CPT1 blocker etomixir on embryonic mice and discovered a reduced number of LEC, further supporting that FAO is necessary for LEC migration and proliferation. In addition, Wong et. al conducted a study that determines the cellular mechanism in which CPT1A drives FAO. They found that decreased CPT1A levels caused a decrease in FAO, which ultimately resulted in reduced LEC proliferation and migration. The authors discovered that CPTA1 is responsible for the production of acetyl-CoA and decreasing CPT1A expression compromises epigenetic modification of lymphangiogenic expression.
The experiments conducted by Wong et. al display evidence for the role of acetyl-CoA in histone acetylation. Data collected from ChIP-seq experiments and co-immunoprecipation show that PROX1 interacts with p300, a histone acetyl transferase, and upregulates FAO by inducing CPT1A expression. They concluded that PROX1 overexpression caused an increase in acetylation of histone p300s and acetylation is contingent upon acetyl-CoA levels.
The results obtained by Wong et. al conclude that lymphatic system development is dependent on acetyl-CoA production by FAO. The decreased expression of CPT1 is suggested to inhibit injury-induced lymphangiogenesis and therefore can act as a pharmacological target. Furthermore, decreased FAO can also inhibit pathological lymphangiogenesis in which can cause dysregulated lymphatic growth that results in metastasis. By unveiling further knowledge about lymphangiogenesis, the impactful discoveries made by Wong et. al, provide information that can lead to innovative pharmacological therapeutics.
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