<br>LncRNA H19 抑制损害肝细胞中内质网-线粒体接触，并通过增加 VDAC1 水平来增强糖异生,Redox Biology

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LncRNA H19 抑制损害肝细胞中内质网-线粒体接触，并通过增加 VDAC1 水平来增强糖异生
Redox Biology ( IF 10.7 ) Pub Date : 2023-12-09 , DOI: 10.1016/j.redox.2023.102989
Arun Nandwani ₁ , Shalu Rathore ₁ , Malabika Datta ₁

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尽管发挥独立的细胞功能，但内质网（ER）和线粒体也在称为线粒体相关 ER 膜（MAM）的特定位点进行物理连接，这些位点由几种在不同的细胞过程中发挥不同作用的束缚蛋白组成。然而，对细胞内这些栓系蛋白的调节研究相对较少。在这里，我们表明糖尿病期间肝脏中的几种 MAM 蛋白发生了显着变化，其中 lncRNA、H19 调节 VDAC1 的水平。使用 H19 特异性 siRNA 抑制 H19 表达改变了 Hepa 1-6 细胞中的 VDAC1、线粒体 Ca2+ 和耗氧率、ATP 和 ROS 水平，并增强了 ER 和线粒体偶联。虽然 H19 抑制不影响脂质积累，但糖异生基因的水平显着增加。H19 抑制增加了 JNK 磷酸化和 IRS1-Ser307 磷酸化，这与 Hepa 1-6 细胞中胰岛素刺激的 AKT （Ser-473）磷酸化和葡萄糖摄取的消除有关。虽然使用 siRNA 和二甲双胍抑制 VDAC1 表达显着挽救了 H19 抑制的作用，但单独过表达 VDAC1 发挥了类似于 H19 抑制的作用，表明 VDAC1 的增加介导了 H19 的不良反应。使用特异性 siRNA 的体内 H19 抑制增加了小鼠肝脏 VDAC1、pJNK 和 pIRS1 （Ser307）水平，并降低了 AKT （Ser-473）磷酸化。这些表明 H19-VDAC1 轴在 ER-线粒体偶联和糖尿病期间肝脏糖异生调节中起重要作用。

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LncRNA H19 inhibition impairs endoplasmic reticulum-mitochondria contact in hepatic cells and augments gluconeogenesis by increasing VDAC1 levels

Inspite of exerting independent cellular functions, the endoplasmic-reticulum (ER) and the mitochondria also physically connect at specific sites termed mitochondria-associated ER membranes (MAMs) and these sites consist of several tethering proteins that play varied roles in diverse cellular processes. However, the regulation of these tethering proteins within the cell is relatively less studied. Here, we show that several MAM proteins are significantly altered in the liver during diabetes and among these, the lncRNA, H19 regulates the levels of VDAC1. Inhibition of H19 expression using H19 specific siRNA altered VDAC1, mitochondrial Ca2+ and oxygen consumption rate, ATP and ROS levels and enhanced ER and mitochondria coupling in Hepa 1–6 cells. While H19 inhibition did not impact lipid accumulation, levels of gluconeogenic genes were significantly increased. JNK-phosphorylation and IRS1-Ser307-phosphorylation were increased by H19 inhibition and this was associated with abrogation of insulin-stimulated AKT (Ser-473) phosphorylation and glucose uptake in Hepa 1–6 cells. While inhibition of VDAC1 expression using siRNAs and with metformin significantly rescued the effects of H19 inhibition, VDAC1 overexpression alone exerted effects similar to H19 inhibition, suggesting that VDAC1 increase mediates the adverse effects of H19. In-vivo H19 inhibition using specific siRNAs increased hepatic VDAC1, pJNK and pIRS1 (Ser307) levels and decreased AKT (Ser-473) phosphorylation in mice. These suggest an important role of the H19-VDAC1 axis in ER-mitochondria coupling and regulation of gluconeogenesis in the liver during diabetes.

更新日期：2023-12-09

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