Loss of Hilnc prevents diet-induced hepatic steatosis through binding of IGF2BP2

Yiao Jiang, Jiayin Peng, Jiawen Song, Juan He, Man Jiang, Jia Wang, Liya Ma, Yuang Wang, Moubin Lin, Hailong Wu, Zhao Zhang, Dong Gao, Yun Zhao

Research output: Contribution to journalArticlepeer-review

Abstract

The Hedgehog (Hh) signalling pathway plays a critical role in regulating liver lipid metabolism and related diseases. However, the underlying mechanisms are poorly understood. Here, we show that the Hh signalling pathway induces a previously undefined long non-coding RNA (Hilnc, Hedgehog signalling-induced long non-coding RNA), which controls hepatic lipid metabolism. Mutation of the Gli-binding sites in the Hilnc promoter region (HilncBM/BM) decreases the expression of Hilnc in vitro and in vivo. HilncBM/BM and Hilnc-knockout mice are resistant to diet-induced obesity and hepatic steatosis through attenuation of the peroxisome proliferator-activated receptor signalling pathway, as Hilnc directly interacts with IGF2BP2 to enhance Pparγ mRNA stability. Furthermore, we identify a potential functional human homologue of Hilnc, h-Hilnc, which has a similar function in regulating cellular lipid metabolism. These findings uncover a critical role of the Hh-Hilnc–IGF2BP2 signalling axis in lipid metabolism and suggest a potential therapeutic target for the treatment of diet-induced hepatic steatosis.

Original languageEnglish (US)
Pages (from-to)1569-1584
Number of pages16
JournalNature Metabolism
Volume3
Issue number11
DOIs
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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