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Vascular endothelial growth factor B promotes transendothelial fatty acid transport into skeletal muscle via histone modifications during catch-up growth.
American Journal of Physiology-Endocrinology and Metabolism ( IF 4.2 ) Pub Date : 2020-09-21 , DOI: 10.1152/ajpendo.00090.2020
Xiaodan Lu 1, 2 , Shengqing Hu 1, 2 , Yunfei Liao 1, 2 , Juan Zheng 1, 2 , Tianshu Zeng 1, 2 , Xueyu Zhong 1, 2 , Geng Liu 1, 2 , Luoning Gou 1, 2 , Lulu Chen 1, 2
Affiliation  

Caloric restriction (CR) followed by refeeding, a phenomenon known as catch-up growth (CUG), results in excessive lipid deposition and insulin resistance in skeletal muscle, but the underlying mechanisms remain elusive. Recent reports have suggested that vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation by regulating endothelial fatty acid transport. Here, we found continuous activation of VEGF-B signaling and increased lipid uptake in skeletal muscle from CR to refeeding, as well as increased lipid deposition and impaired insulin sensitivity after refeeding in the skeletal muscle of CUG rodents. Inhibiting VEGF-B signaling ameliorated fatty acid uptake in and transport across endothelial cells. Knockdown of Vegfb in the tibialis anterior (TA) muscle of CUG mice significantly attenuated muscle lipid accumulation and improved muscle insulin signaling by decreasing lipid uptake. Furthermore, we showed that aberrant histone methylation (H3K9me1) and acetylation (H3K14ac and H3K18ac) at the Vegfb promoter might be the main cause of persistent VEGF-B up-regulation in skeletal muscle during CUG. Modifying these aberrant loci using their related enzymes (PHF2 or P300) could regulate VEGF-B expression in vitro. Collectively, our findings indicate that VEGF-B can promote transendothelial lipid transport and led to lipid overaccumulation and impaired insulin signaling in skeletal muscle during CUG, which might be mediated by histone methylation and acetylation.

中文翻译:

血管内皮生长因子B在追赶性生长过程中通过组蛋白修饰促进跨内皮脂肪酸向骨骼肌的转运。

热量限制(CR)再进食(一种称为追赶生长(CUG))现象,会导致骨骼肌中过多的脂质沉积和胰岛素抵抗,但潜在的机制仍然难以捉摸。最近的报道表明,血管内皮生长因子B(VEGF-B)通过调节内皮脂肪酸的运输来控制肌肉脂质的积累。在这里,我们发现CUG啮齿动物的骨骼肌从CR到重新进食后,VEGF-B信号传导的持续激活和脂质在骨骼肌中的摄取增加,以及脂质进食后骨骼沉积中脂质沉积增加和胰岛素敏感性受损。抑制VEGF-B信号改善了脂肪酸在内皮细胞中的吸收和转运。降低CUG小鼠胫前(TA)肌肉中Vegfb的表达,可通过减少脂质摄取来显着减弱肌肉脂质蓄积并改善肌肉胰岛素信号传导。此外,我们显示,Vegfb启动子处异常的组蛋白甲基化(H3K9me1)和乙酰化(H3K14ac和H3K18ac)可能是CUG期间骨骼肌中VEGF-B持续上调的主要原因。使用它们的相关酶(PHF2或P300)修饰这些异常基因座可以在体外调节VEGF-B的表达。总的来说,我们的研究结果表明,VEGF-B可以促进CUG期间骨骼肌的跨内皮脂质运输,并导致脂质过度积聚和受损的胰岛素信号传导,这可能是由组蛋白甲基化和乙酰化介导的。我们发现,Vegfb启动子处异常的组蛋白甲基化(H3K9me1)和乙酰化(H3K14ac和H3K18ac)可能是CUG期间骨骼肌中VEGF-B持续上调的主要原因。使用它们的相关酶(PHF2或P300)修饰这些异常基因座可以在体外调节VEGF-B的表达。总的来说,我们的发现表明,VEGF-B可以促进跨内皮脂质转运,并导致CUG期间骨骼肌中脂质过度积累和胰岛素信号转导受损,这可能是由组蛋白甲基化和乙酰化介导的。我们发现,Vegfb启动子处异常的组蛋白甲基化(H3K9me1)和乙酰化(H3K14ac和H3K18ac)可能是CUG期间骨骼肌中VEGF-B持续上调的主要原因。使用它们的相关酶(PHF2或P300)修饰这些异常基因座可以在体外调节VEGF-B的表达。总的来说,我们的研究结果表明,VEGF-B可以促进CUG期间骨骼肌的跨内皮脂质运输,并导致脂质过度积累和胰岛素信号传导受损,这可能是由组蛋白甲基化和乙酰化介导的。使用它们的相关酶(PHF2或P300)修饰这些异常基因座可以在体外调节VEGF-B的表达。总的来说,我们的研究结果表明,VEGF-B可以促进CUG期间骨骼肌的跨内皮脂质运输,并导致脂质过度积聚和受损的胰岛素信号传导,这可能是由组蛋白甲基化和乙酰化介导的。使用它们的相关酶(PHF2或P300)修饰这些异常基因座可以在体外调节VEGF-B的表达。总的来说,我们的研究结果表明,VEGF-B可以促进CUG期间骨骼肌的跨内皮脂质运输,并导致脂质过度积聚和受损的胰岛素信号传导,这可能是由组蛋白甲基化和乙酰化介导的。
更新日期:2020-09-22
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