Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation

Jun Guo, Weiwei Fang, Libo Sun, Yonggang Lu, Lin Dou, Xiuqing Huang, Weiqing Tang, Liqing Yu () and Jian Li ()
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Jun Guo: National Center of Gerontology
Weiwei Fang: National Center of Gerontology
Libo Sun: Capital Medical University
Yonggang Lu: National Center of Gerontology
Lin Dou: National Center of Gerontology
Xiuqing Huang: National Center of Gerontology
Weiqing Tang: National Center of Gerontology
Liqing Yu: Georgia State University
Jian Li: National Center of Gerontology

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03072-8

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