Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven B-3000, Belgium.
Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven B-3000, Belgium.
Nature. 2017 Feb 2;542(7639):49-54. doi: 10.1038/nature21028. Epub 2016 Dec 26.
Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid β-oxidation, impairs lymphatic development. LECs use fatty acid β-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid β-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo.
淋巴管由淋巴管内皮细胞（LEC）组成，对健康至关重要。然而，代谢在淋巴管发育中的作用尚未阐明。在这里，我们报告在转基因小鼠模型中，脂肪酸β-氧化的限速酶 CPT1A 在 LEC 中的特异性缺失会损害淋巴管的发育。LEC 利用脂肪酸β-氧化来增殖，并在 LEC 分化过程中进行淋巴标记物表达的表观遗传调控。在机制上，转录因子 PROX1 上调 CPT1A 的表达，从而增加依赖于脂肪酸β-氧化的乙酰辅酶 A 的产生。乙酰辅酶 A 被组蛋白乙酰转移酶 p300 用于在淋巴管生成基因上乙酰化组蛋白。PROX1-p300 相互作用促进 PROX1 靶基因的优先组蛋白乙酰化。通过这种依赖代谢的机制，PROX1 介导促进淋巴管生成的表观遗传变化。值得注意的是，CPT1 酶的阻断抑制损伤诱导的淋巴管生成，并且通过补充乙酸来补充乙酰辅酶 A 可在体内挽救这一过程。
