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The role of fatty acid beta-oxidation in lymphangiogenesis

机译：脂肪酸β-氧化在淋巴管生成中的作用

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摘要

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 beta-oxidation, impairs lymphatic development. LECs use fatty acid beta-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 beta-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.
机译：淋巴管衬有淋巴管内皮细胞（LEC），对健康至关重要。但是，尚未阐明代谢在淋巴发育中的作用。在这里，我们报道在转基因小鼠模型中，LEC特异性CPT1A的丢失（一种脂肪酸β-氧化中的速率控制酶）损害了淋巴的发育。 LEC在LEC分化过程中使用脂肪酸β-氧化来增殖和用于表观遗传调控淋巴标记的表达。从机制上讲，转录因子PROX1上调CPT1A表达，从而增加了依赖于脂肪酸β-氧化的乙酰辅酶A的产生。组蛋白乙酰转移酶p300使用乙酰辅酶A在淋巴管生成基因处乙酰化组蛋白。 PROX1-p300的相互作用促进了PROX1靶基因的优先组蛋白乙酰化。通过这种依赖于代谢的机制，PROX1介导表观遗传学变化，从而促进淋巴管生成。值得注意的是，CPT1酶的阻滞抑制了损伤诱导的淋巴管生成，通过补充乙酸盐补充乙酰辅酶A可以在体内挽救这一过程。

著录项

  • 来源
    《Nature》 |2017年第7639期|49-54|共6页
  • 作者

    Wong Brian W.; Wang Xingwu; Zecchin Annalisa; Thienpont Bernard; Cornelissen Ivo; Kalucka Joanna; Garcia-Caballero Melissa; Missiaen Rindert; Huang Hongling; Burning Ulrike; Blacher Silvia; Vinckier Stefan; Goveia Jermaine; Knobloch Marlen; Zhao Hui; Dierkes Cathrin; Shi Chenyan; Haegerling Rene; Moral-Darde Veronica; Wyns Sabine; Lippens Martin; Jessberger Sebastian; Fendt Sarah-Maria; Luttun Aernout; Noel Agnes; Kiefer Friedemann; Ghesquiere Bart; Moons Lieve; Schoonjans Luc; Dewerchin Mieke; Eelen Guy; Lambrechts Diether; Carmeliet Peter;

  • 作者单位

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Translat Genet, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Univ Liege, GIGA Canc, Lab Biol Tumor & Dev, B-4000 Liege, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Translat Genet, B-3000 Leuven, Belgium;

    Max Planck Inst Mol Biomed, Dept Vasc Cell Biol, Mammalian Cell Signaling Lab, D-48161 Munster, Germany;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Max Planck Inst Mol Biomed, Dept Vasc Cell Biol, Mammalian Cell Signaling Lab, D-48161 Munster, Germany;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Metabol Core Facil, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Univ Zurich, Brain Res Inst, Fac Med & Sci, CH-8057 Zurich, Switzerland;

    VIB, VIB Vesalius Res Ctr, Lab Cellular Metab & Metab Regulat, B-3000 Leuven, Belgium|Katholieke Univ Leuven, Dept Oncol, Lab Cellular Metab & Metab Regulat, B-3000 Leuven, Belgium|Leuven Canc Inst LKI, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Cardiovasc Sci, Ctr Mol & Vasc Biol, B-3000 Leuven, Belgium;

    Max Planck Inst Mol Biomed, Dept Vasc Cell Biol, Mammalian Cell Signaling Lab, D-48161 Munster, Germany;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|Katholieke Univ Leuven, Dept Biol, Anim Physiol & Neurobiol Sect, Lab Neural Circuit Dev & Regenerat, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Translat Genet, B-3000 Leuven, Belgium;

    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium|VIB, VIB Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;

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