Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; and.
Department of Environmental Health Sciences, School of Public Health, Yale University, New Haven, Connecticut, USA.
FASEB J. 2019 Oct;33(10):11411-11419. doi: 10.1096/fj.201900643RRR. Epub 2019 Jul 16.
Nonalcoholic fatty liver disease (NAFLD), which has an unknown pathogenesis and lacks a curative treatment, is becoming more prevalent. A previous long noncoding RNA (lncRNA) profiling analysis revealed a potential role for fatty liver-related lncRNA 2 (FLRL2) in the pathogenesis of NAFLD. To further understand the role of FLRL2 in NAFLD and explore its therapeutic value, both and NAFLD models were constructed. Small interfering RNA and small hairpin RNA interference and adenovirus transfection were adopted to manipulate the expressions of FLRL2, aryl-hydrocarbon receptor nuclear translocator-like (Arntl), and sirtuin 1 (Sirt1) expression. Steatosis was evaluated through histologic staining with hematoxylin and eosin and oil red O and also by quantitative triglyceride measurements. FLRL2 is a widely distributed nuclear lncRNA that is down-regulated in NAFLD. Overexpression of FLRL2 resolved steatosis, lipogenesis, inflammation, and endoplasmic reticulum (ER) stress in NAFLD, and down-regulation of FLRL2 resulted in the opposite effects. Sequence analysis demonstrated that FLRL2 was located in the intronic region of the Arntl gene, and a luciferase assay showed transcriptional activation of the Arntl gene upon FLRL2 overexpression. A similar expression pattern and synergistic effect of Arntl manipulation was observed in NAFLD . Inhibition of Arntl partially reversed the steatosis amelioration induced by FLRL2 overexpression. Downstream Sirt1 was also inhibited in NAFLD and influenced by both FLRL2 and Arntl. In NAFLD mice, FLRL2 enhancement alleviated steatosis, activated the Arntl-Sirt1 axis, and inhibited lipogenesis, ER stress, and inflammation, providing preliminary evidence of the benefits of FLRL2-mediated gene therapy in NAFLD.-Chen, Y., Chen, X., Gao, J., Xu, C., Xu, P., Li, Y., Zhu, Y., Yu, C. Long noncoding RNA FLRL2 alleviated nonalcoholic fatty liver disease through Arntl-Sirt1 pathway.
非酒精性脂肪性肝病（NAFLD）的发病机制尚不清楚，也缺乏有效的治疗方法，其发病率正逐渐升高。先前的长非编码 RNA（lncRNA）分析表明，脂肪性肝病相关 lncRNA 2（FLRL2）在 NAFLD 的发病机制中可能发挥作用。为了进一步了解 FLRL2 在 NAFLD 中的作用并探索其治疗价值，构建了 和 两种 NAFLD 模型。采用小干扰 RNA 和短发夹 RNA 干扰及腺病毒转染来操纵 FLRL2、芳香烃受体核转位样（Arntl）和沉默调节蛋白 1（Sirt1）的表达。通过苏木精和伊红及油红 O 染色和定量甘油三酯测量评估脂肪变性。FLRL2 是一种广泛分布的核 lncRNA，在 NAFLD 中下调。FLRL2 的过表达可改善 NAFLD 中的脂肪变性、脂肪生成、炎症和内质网（ER）应激，而下调 FLRL2 则产生相反的效果。序列分析表明，FLRL2 位于 Arntl 基因的内含子区域，荧光素酶报告基因检测显示 FLRL2 过表达可激活 Arntl 基因的转录。在 NAFLD 中观察到 Arntl 操作的类似表达模式和协同效应。Arntl 的抑制部分逆转了 FLRL2 过表达引起的脂肪变性改善。在 NAFLD 中，下游的 Sirt1 也受到抑制，并受到 FLRL2 和 Arntl 的影响。在 NAFLD 小鼠中，FLRL2 的增强可减轻脂肪变性，激活 Arntl-Sirt1 轴，并抑制脂肪生成、ER 应激和炎症，为 FLRL2 介导的基因治疗在 NAFLD 中的益处提供了初步证据。-Chen, Y., Chen, X., Gao, J., Xu, C., Xu, P., Li, Y., Zhu, Y., Yu, C. Long noncoding RNA FLRL2 alleviated nonalcoholic fatty liver disease through Arntl-Sirt1 pathway.
