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

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

来源：Cellular and Molecular Gastroenterology and Hepatology, 2022, 13(5): 1393-1412.

DOI：10.1016/j.jcmgh.2022.01.016

• miR-23b
• 27b
• 24-1 Cluster
• TGF-
• 52
• Gremlin1
• LOX
• Itg? 2
• 5
• Hepatic Stellate Cells
• Hepatic Fibrosis

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-/5 (TGF-/5) signaling during hepatic development prompted us to explore whether this cluster inhibits HSC activation and hepatic fibrosis. METHODS: Experimental fibrosis was studied in carbon tet-rachloride (CCl4)-treated C57BL/6 mice. After administration of miR-23b/27b/24-1 lentivirus or vehicle, animals were eutha-nized 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 tar-geted messenger RNAs, which reduced the protein expression of 5 secretory profibrotic genes (TGF-/52, Gremlin1, LOX, Itga2, and Itga5) in HSCs. Suppression of the TGF-/5 signaling pathway by down-regulation of TGF-/52, Itga2, and Itga5, and activation of the bone morphogenetic protein signaling pathway by inhi-bition of Gremlin1, decreased extracellular matrix secretion of HSCs. Furthermore, down-regulation of LOX expression soft-ened the ECM. Moreover, a reduction in tissue inhibitors of metalloproteinase 1 expression owing to weakened TGF-/5 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. (Cell Mol Gastroenterol Hepatol 2022;13:1393-1412; https://doi.org/ 10.1016/j.jcmgh.2022.01.016)

• 单位
  中国医学科学院; 中国医学科学院北京协和医院; 武汉大学