Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
VIB Center for Cancer Biology Research, Leuven, Belgium.
Autophagy. 2023 Apr;19(4):1351-1353. doi: 10.1080/15548627.2022.2117513. Epub 2022 Sep 1.
Lymphatic endothelial cells (LECs) exploit fatty acid oxidation (FAO) to grow and to maintain lymphatic vessel identity through the epigenetic regulation of the essential transcription factor PROX1. In our recent study, we found that LEC-specific loss of prevents injury-induced lymphangiogenesis . Inadequate degradation of lipid droplets (LDs) caused by genetic ablation of in LECs disturbs mitochondrial fitness, and reduces mitochondrial FAO and acetyl-CoA levels, ultimately affecting PROX1-mediated epigenetic regulation of CPT1A and key lymphatic markers, most importantly FLT4/VEGFR3. Supplementing the fatty acid precursor acetate rescues defective inflammation-driven lymphangiogenesis in LEC-specific knockout mice. Thus, efficient macroautophagy/autophagy-mediated LD breakdown is critical to maintain mitochondrial metabolism and acetyl-CoA levels, which sustain a PROX1-mediated lymphatic gene program required for LEC identity and inflammation-driven lymphangiogenesis.
淋巴管内皮细胞 (LEC) 通过关键转录因子 PROX1 的表观遗传调控，利用脂肪酸氧化 (FAO) 来生长和维持淋巴管的特性。在我们最近的研究中，我们发现 LEC 特异性缺失 可预防损伤诱导的淋巴管生成 。由于 LEC 中 的遗传缺失导致脂质滴 (LD) 不能充分降解，从而扰乱了线粒体的适应性，并降低了线粒体 FAO 和乙酰辅酶 A 水平，最终影响了 PROX1 介导的 CPT1A 和关键淋巴管标志物的表观遗传调控，最重要的是 FLT4/VEGFR3。补充脂肪酸前体醋酸盐可挽救 LEC 特异性 敲除小鼠中缺陷的炎症驱动的淋巴管生成。因此，有效的巨自噬/自噬介导的 LD 分解对于维持线粒体代谢和乙酰辅酶 A 水平至关重要，这些水平维持了 PROX1 介导的淋巴管基因程序，该程序对于 LEC 特性和炎症驱动的淋巴管生成是必需的。
