Guo Jun, Fang Weiwei, Sun Libo, Lu Yonggang, Dou Lin, Huang Xiuqing, Tang Weiqing, Yu Liqing, Li Jian
The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.
Nat Commun. 2018 Feb 9;9(1):612. doi: 10.1038/s41467-018-03072-8.
Ultraconserved (uc) RNAs, a class of long non-coding RNAs (lncRNAs), are conserved across humans, mice, and rats, but the physiological significance and pathological role of ucRNAs is largely unknown. Here we show that uc.372 is upregulated in the livers of db/db mice, HFD-fed mice, and NAFLD patients. Gain-of-function and loss-of-function studies indicate that uc.372 drives hepatic lipid accumulation in mice by promoting lipogenesis. We further demonstrate that uc.372 binds to pri-miR-195/pri-miR-4668 and suppresses maturation of miR-195/miR-4668 to regulate expression of genes related to lipid synthesis and uptake, including ACC, FAS, SCD1, and CD36. Finally, we identify that uc.372 is located downstream of the insulinoma-associated 2 (INSM2) gene that is transcriptionally activated by upstream transcription factor 1 (USF1). Our findings reveal a novel mechanism by which uc.372 drives hepatic steatosis through inhibition of miR-195/miR-4668 maturation to relieve miR-195/miR-4668-mediated suppression of functional target gene expression.
超保守（uc）RNAs是一类长链非编码RNA（lncRNAs），在人类、小鼠和大鼠中具有保守性，但ucRNAs的生理意义和病理作用在很大程度上尚不清楚。在此我们表明，uc.372在db/db小鼠、高脂饮食喂养的小鼠和非酒精性脂肪性肝病（NAFLD）患者的肝脏中上调。功能获得和功能丧失研究表明，uc.372通过促进脂肪生成驱动小鼠肝脏脂质积累。我们进一步证明，uc.372与pri-miR-195/pri-miR-4668结合并抑制miR-195/miR-4668的成熟，以调节与脂质合成和摄取相关的基因表达，包括乙酰辅酶A羧化酶（ACC）、脂肪酸合酶（FAS）、硬脂酰辅酶A去饱和酶1（SCD1）和脂肪酸转运蛋白CD36。最后，我们确定uc.372位于胰岛素瘤相关2（INSM2）基因的下游，该基因由上游转录因子1（USF1）转录激活。我们的研究结果揭示了一种新机制，即uc.372通过抑制miR-195/miR-4668成熟来缓解miR-195/miR-4668介导的对功能靶基因表达的抑制，从而驱动肝脏脂肪变性。
