Graphene Oxide Causes Disordered Zonation Due to Differential Intralobular Localization in the Liver.,ACS Nano

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Graphene Oxide Causes Disordered Zonation Due to Differential Intralobular Localization in the Liver.
ACS Nano ( IF 15.8 ) Pub Date : 2020-01-06 , DOI: 10.1021/acsnano.9b08127
Yakun Wu _{1,

2} , Wenya Feng _{1,

2} , Rui Liu _{1,

2} , Tian Xia ₃ , Sijin Liu _{1,

2}

Affiliation

The liver is the primary organ to sequester nanodrugs, representing a substantial hurdle for drug delivery and raising toxicity concerns. However, the mechanistic details underlying the liver sequestration and effects on the liver are still elusive. The difficulty in studying the liver lies in its complexity, which is structured with stringently organized anatomical units called lobules. Graphene oxide (GO) has attracted attention for its applications in biomedicine, especially as a nanocarrier; however, its sequestration and effects in the liver, the major enrichment and metabolic organ, are less understood. Herein, we unveiled the differential distribution of GO in lobules in the liver, with a higher amount surrounding portal triad zones than the central vein zones. Strikingly, liver zonation patterns also changed, as reflected by changes in vital zonated genes involved in hepatocyte integrity and metabolism, leading to compromised hepatic functions. RNA-Seq and DNA methylation sequencing analyses unraveled that GO-induced changes in liver functional zonation could be ascribed to dysregulation of key signaling pathways governing liver zonation at not only mRNA transcriptions but also DNA methylation imprinting patterns, partially through TET-dependent signaling. Together, this study reveals the differential GO distribution pattern in liver lobules and pinpoints the genetic and epigenetic mechanisms in GO-induced liver zonation alterations.

中文翻译：

氧化石墨烯由于肝脏中不同的小叶内局限性而导致无序区带。

肝脏是螯合纳米药物的主要器官，代表了药物输送和引起毒性问题的重大障碍。但是，肝脏螯合和对肝脏的影响的机制细节仍然难以捉摸。研究肝脏的困难在于其复杂性，该结构由称为小叶的严格组织的解剖单元构成。氧化石墨烯（GO）在生物医学中的应用引起了人们的关注，特别是作为纳米载体。然而，人们对它在肝脏，主要的富集和代谢器官中的螯合作用和作用知之甚少。在本文中，我们揭示了肝小叶中GO的差异分布，其中门三联征区周围的量高于中央静脉区。令人惊讶的是，肝脏分区模式也发生了变化，反映在参与肝细胞完整性和代谢的重要分区基因变化中，导致肝功能受损。RNA-Seq和DNA甲基化测序分析揭示，GO诱导的肝功能区带变化可能归因于主要通过TET依赖性信号传导控制肝区带化的关键信号通路失调，不仅是mRNA转录，还有DNA甲基化印迹模式。总之，这项研究揭示了肝小叶中不同的GO分布模式，并指出了GO诱导的肝区带改变中的遗传和表观遗传机制。RNA-Seq和DNA甲基化测序分析揭示，GO诱导的肝功能区带变化可能归因于主要通过TET依赖性信号传导控制肝区带化的关键信号通路失调，不仅是mRNA转录，还有DNA甲基化印迹模式。总之，这项研究揭示了肝小叶中不同的GO分布模式，并指出了GO诱导的肝区带改变中的遗传和表观遗传机制。RNA-Seq和DNA甲基化测序分析揭示，GO诱导的肝功能区带变化可能归因于主要通过TET依赖性信号传导控制肝区带化的关键信号通路失调，不仅是mRNA转录，还有DNA甲基化印迹模式。总之，这项研究揭示了肝小叶中不同的GO分布模式，并指出了GO诱导的肝区带改变中的遗传和表观遗传机制。

更新日期：2020-01-06

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