Potential role of Hedgehog signaling and microRNA-29 in liver fibrosis of IKKβ-deficient mouse

J Mol Histol. 2014 Feb;45(1):103-12. doi: 10.1007/s10735-013-9532-5. Epub 2013 Aug 15.

Abstract

Recent studies have reported that NF-κB mediated down-regulation of miRNA-29 and lower expression of miRNA-29 promoted the deposition of collagens in fibrotic liver. Our previous research demonstrated that the increased Hedgehog (Hh) signaling, a key regulator for hepatic fibrogenesis, induced the severe hepatic fibrosis in the livers with impaired NF-κB signaling. These findings led us to investigate the effect of Hh and miRNA-29 on the hepatic fibrosis under dysregulated NF-κB signaling. In this study, we used IKKβ(F/F) and IKKβ-deficient IKKβ(ΔHEP) mouse model with a defective NF-κB signaling pathway, and assessed the expression of the miRNA-29 family (miRNA-29a, miRNA-29b, and miRNA-29c), Hh, and proliferation of MF-HSCs in liver from IKKβ(F/F) mice and IKKβ(ΔHEP) mice both before and after MCDE treatment. The activation of NF-κB was significantly increased in MCDE diet-fed IKKβ(F/F) mice compared to IKKβ(ΔHEP) mice. Expression of miRNA-29 family was greater in MCDE diet-fed IKKβ(ΔHEP) mice than IKKβ(F/F) mice, demonstrating that the impaired NF-κB pathway was unable to suppress the expression of miRNA-29s after injury. However, expression of the Hh signaling pathway was greatly enhanced, and activation of Hh promoted the accumulation of MF-HSCs with impaired NF-κB, eventually increasing fibrogenesis in the damaged liver of IKKβ(ΔHEP) mice. Therefore, these results demonstrated that Hh signaling regulates the proliferation of MF-HSCs irrespective of the action of miRNA-29, eventually contributing hepatic fibrosis, when the NF-κB pathway is disrupted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition
  • Gene Expression
  • Hedgehog Proteins / metabolism*
  • Hepatic Stellate Cells / metabolism
  • I-kappa B Kinase / deficiency*
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • NF-kappa B / metabolism
  • Signal Transduction*

Substances

  • Hedgehog Proteins
  • MIRN29 microRNA, mouse
  • MicroRNAs
  • NF-kappa B
  • I-kappa B Kinase
  • Ikbkb protein, mouse