Cellular and Molecular Gastroenterology and Hepatology (Jan 2022)

The miR-23b/27b/24-1 Cluster Inhibits Hepatic Fibrosis by Inactivating Hepatic Stellate CellsSummary

  • Lin-Yan Wan,
  • Hu Peng,
  • Yi-Ran Ni,
  • Xue-Ping Jiang,
  • Jiao-Jiao Wang,
  • Yan-Qiong Zhang,
  • Lan Ma,
  • Rui Li,
  • Lin Han,
  • Yong Tan,
  • Jun-Ming Li,
  • Wen-Li Cai,
  • Wen-Fang Yuan,
  • Jia-Jie Liang,
  • Lu Huang,
  • Xu Wu,
  • Quan Zhou,
  • Qi-Ni Cheng,
  • Xue Yang,
  • Meng-Yuan Liu,
  • Wen-Bing Ai,
  • Chang-Bai Liu,
  • Hongbing Zhang,
  • Jiang-Feng Wu

Journal volume & issue
Vol. 13, no. 5
pp. 1393 – 1412

Abstract

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Background & Aims: Hepatic fibrosis is characterized by hepatic stellate cell (HSC) activation and transdifferentiation-mediated extracellular matrix (ECM) deposition, which both contribute to cirrhosis. However, no antifibrotic regimen is available in the clinic. microRNA-23b/27b/24-1 cluster inhibition of transforming growth factor-β (TGF-β) signaling during hepatic development prompted us to explore whether this cluster inhibits HSC activation and hepatic fibrosis. Methods: Experimental fibrosis was studied in carbon tetrachloride (CCl4)-treated C57BL/6 mice. After administration of miR-23b/27b/24-1 lentivirus or vehicle, animals were euthanized for liver histology. In primary rat HSC and HSC-T6, the anti-fibrotic effect of miR-23b/27b/24-1 cluster was furtherly investigated by RNA-sequencing, luciferase reporter assay, western blotting and bioinformatic means. Results: In this study, we showed that increasing the miR-23b/27b/24-1 level through intravenous delivery of miR-23b/27b/24-1 lentivirus ameliorated mouse hepatic fibrosis. Mechanistically, the miR-23b/27b/24-1 cluster directly targeted messenger RNAs, which reduced the protein expression of 5 secretory profibrotic genes (TGF-β2, Gremlin1, LOX, Itgα2, and Itgα5) in HSCs. Suppression of the TGF-β signaling pathway by down-regulation of TGF-β2, Itgα2, and Itgα5, and activation of the bone morphogenetic protein signaling pathway by inhibition of Gremlin1, decreased extracellular matrix secretion of HSCs. Furthermore, down-regulation of LOX expression softened the ECM. Moreover, a reduction in tissue inhibitors of metalloproteinase 1 expression owing to weakened TGF-β signaling increased ECM degradation. Conclusions: Hepatic overexpression of the miR-23b/27b/24-1 cluster blocked hepatic fibrosis and may be a novel therapeutic regimen for patients with hepatic fibrosis.

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