Xin Mingyang, Guo Qian, Lu Qingchun, Lu Juan, Wang Po-Shun, Dong Yun, Li Tao, Chen Ye, Gerhard Glenn S, Yang Xiao-Feng, Autieri Michael, Yang Ling
Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Department of Intensive Care Unit, The First Hospital of Jilin University, Changchun, 130021, China.
Cell Biosci. 2021 Dec 14;11(1):208. doi: 10.1186/s13578-021-00722-1.
The majority of mammalian genome is composed of non-coding regions, where numerous long non-coding RNAs (lncRNAs) are transcribed. Although lncRNAs have been identified to regulate fundamental biological processes, most of their functions remain unknown, especially in metabolic homeostasis. Analysis of our recent genome-wide screen reveals that Gm15441, a thioredoxin-interacting protein (Txnip) antisense lncRNA, is the most robustly induced lncRNA in the fasting mouse liver. Antisense lncRNAs are known to regulate their sense gene expression. Given that Txnip is a critical metabolic regulator of the liver, we aimed to investigate the role of Gm15441 in the regulation of Txnip and liver metabolism.
We examined the response of Gm15441 and Txnip under in vivo metabolic signals such as fasting and refeeding, and in vitro signals such as insulin and key metabolic transcription factors. We investigated the regulation of Txnip expression by Gm15441 and the underlying mechanism in mouse hepatocytes. Using adenovirus-mediated liver-specific overexpression, we determined whether Gm15441 regulates Txnip in the mouse liver and modulates key aspects of liver metabolism.
We found that the expression levels of Gm15441 and Txnip showed a similar response pattern to metabolic signals in vivo and in vitro, but that their functions were predicted to be opposite. Furthermore, we found that Gm15441 robustly reduced Txnip protein expression in vitro through sequence-specific regulation and translational inhibition. Lastly, we confirmed the Txnip inhibition by Gm15441 in vivo (mice) and found that Gm15441 liver-specific overexpression lowered plasma triglyceride and blood glucose levels and elevated plasma ketone body levels.
Our data demonstrate that Gm15441 is a potent Txnip inhibitor and a critical metabolic regulator in the liver. This study reveals the therapeutic potential of Gm15441 in treating metabolic diseases.
大多数哺乳动物基因组由非编码区组成，在这些区域转录出了大量的长链非编码RNA（lncRNA）。尽管已发现lncRNA可调节基本生物学过程，但其大多数功能仍不清楚，尤其是在代谢稳态方面。对我们最近全基因组筛选的分析表明，Gm15441，一种与硫氧还蛋白相互作用蛋白（Txnip）的反义lncRNA，是禁食小鼠肝脏中诱导最强烈的lncRNA。已知反义lncRNA可调节其正义基因的表达。鉴于Txnip是肝脏的关键代谢调节因子，我们旨在研究Gm15441在调节Txnip和肝脏代谢中的作用。
我们检测了Gm15441和Txnip在体内代谢信号（如禁食和再喂食）以及体外信号（如胰岛素和关键代谢转录因子）作用下的反应。我们研究了Gm15441对小鼠肝细胞中Txnip表达的调节及其潜在机制。通过腺病毒介导的肝脏特异性过表达，我们确定了Gm15441是否在小鼠肝脏中调节Txnip并调节肝脏代谢的关键方面。
我们发现Gm15441和Txnip的表达水平在体内和体外对代谢信号呈现出相似的反应模式，但其功能预计相反。此外，我们发现Gm15441在体外通过序列特异性调节和翻译抑制显著降低了Txnip蛋白表达。最后，我们在体内（小鼠）证实了Gm15441对Txnip的抑制作用，并发现Gm15441肝脏特异性过表达降低了血浆甘油三酯和血糖水平，提高了血浆酮体水平。
我们的数据表明，Gm15441是一种有效的Txnip抑制剂，是肝脏中的关键代谢调节因子。这项研究揭示了Gm15441在治疗代谢性疾病方面的治疗潜力。
