State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
J Environ Sci (China). 2019 Nov;85:138-146. doi: 10.1016/j.jes.2019.05.019. Epub 2019 May 24.
Arsenic (As) is an omnipresent metalloid toxicant, which has elicited serious environmental pollution and health risky problems. Previous studies have uncovered that the As exposure could also cause markedly reduction of serum triglycerides in mice. However, the regulation mechanisms are still largely unknown. The present study is aimed to elucidate the molecular mechanisms of lncRNAs in As-induced lipid metabolic disequilibrium. We demonstrated that lncRNA PU.1 AS was significantly induced in the liver of As-feed mice companied with lower serum triglycerides contents; further in vitro experiment confirmed that PU.1 AS regulated liver cells lipid accumulation by nile red fluorescence staining. Intensive mechanistic investigations illustrated that PU.1 AS could interact with EZH2 protein to regulate its downstream target gene expression, and As-induced PU.1 AS attenuated EZH2-supppressed Sirt6 expression, thereafter leading to a decreased SREBP-1c protein expression, as well as the diminished synthesis of triglycerides in hepatocytes. In conclusion, this study provided a new lncRNA-related regulatory signaling pathway participating in As-induced abnormal lipid metabolism.
砷（As）是一种普遍存在的类金属毒物，已引发严重的环境污染和健康风险问题。先前的研究表明，砷暴露还会导致小鼠血清甘油三酯明显降低。然而，其调节机制在很大程度上尚不清楚。本研究旨在阐明 lncRNA 在砷诱导的脂质代谢失衡中的分子机制。我们发现，长链非编码 RNA PU.1 AS 在喂食砷的小鼠肝脏中显著诱导，伴随着血清甘油三酯含量降低；进一步的体外实验证实，PU.1 AS 通过尼罗红荧光染色调节肝细胞脂质积累。深入的机制研究表明，PU.1 AS 可以与 EZH2 蛋白相互作用，调节其下游靶基因的表达，砷诱导的 PU.1 AS 减弱了 EZH2 抑制的 Sirt6 表达，进而导致 SREBP-1c 蛋白表达减少，以及肝细胞中甘油三酯合成减少。总之，本研究提供了一条新的 lncRNA 相关调控信号通路，参与砷诱导的异常脂质代谢。
