Published in Nature, “The role of fatty acid β-oxidation in lymphangiogenesis” by Wong et al. crossed biological and chemistry disciplines in producing a new model of genetic regulation between regulatory genes in lymphatic endothelial cell (LEC) development and the fatty acid oxidation of metabolism. Before the publishing of their work there had been no previously established relationship between metabolic regulation and lymphangiogenesis. They established a crucial role of the molecule acetyl CoA (obtained from the FAO pathway) to be used for acetylation on the LEC-differentiation transcription factor, PROX1.
The medical and disease-related applications of their model are varied, given that the lymph system is integral to human functionality. The beginning of the authors’ exploration in lymphangiogenesis began with investigating an observed positive correlation between FAO rates and LECs (compared to other endothelial cell types). This was established by assessing carnitine palmitoyltransferase (CPT) enzyme expression in LECs and their precursors, venous endothelial cells (VEC). They then produced evidence for a relationship between the CPT1A activity and VEC from LEC differentiation. Lymphangiogenesis was marked by studying the transcription factor PROX1 which is critical for the VEC-to-LEC process. Additionally, the study of transgenic mice populations mutant in Cpt1a, Prox1, and Cpt1a;Prox1 established the CPT1A enzyme of FAO as a factor in the control of lymphatics. This was confirmed again in a drug experiment using the CPT1 blocker, etomoxir, which confirmed localized lymphatic defects in vivo.
Beyond just posing a relationship between CPT1A and PROX1 as LEC-regulating enzymes, the authors reported multiple pieces of evidence for FAO regulation of LEC differentation. Knockdowns in the cpt1a gene resuted in altered functionality of LEC tissue, leading to overall lymphatic defects in mouse embryos. Defects in CPT1A resulted in the same observable outcomes as etomoxir, leading the authors to hypothesize the role of acetyl-CoA generated in the FAO as a genetic expression regulator in LECs.
Support for this hypothesis came ChIP-seq experiments that showed two PROX1 binding sites in Cpt1a, and a positive correlation between PROX1 activity and CPT1A expression. Experiments showed that PROX1 has interactions with the histone acetylation enzyme p300. The authors observed that acetyl-CoA/CoA ratios were altered when PROX1 was overexpressed, and by contrast CPT1A alteration resulted in a decreased ratio. This led them to propose that carbons from acetyl-CoA of the FAO were being used by p300 to regulate PROX1 expression.
This paper presented a model of PROX1 regulation by the metabolic pathway that did not challenge the previously established knowledge of PROX1 role in LEC development. They held that PROX1 induces expression of CPT1A which results in acetyl-CoA derived from the FAO pathway. The carbons of acetyl-CoA are used by p300 to enhance prox1 expresssion because acetylation of the histone tails results in relaxation of binding, allowing genes to become accessible to transcription factors. The second part of their mechanistic model is that PROX1 interactions with p300 also results in “more selective and effective” lymphatic gene expression. They propose that PROX1 does this more selection by preferentially recruiting histone acetyltransferases to its targeted genes.
The contents of this paper touched subjects of embryogenesis, genomics, chemical analysis, medical applications, genetics, etc. The result was a body of work that presented a novel regulatory mechanism between FAO metabolic activity and lymphangiogenesis which has many applications to pharmaceuticals and disease.
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