MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression

• Published in: Nature communications Vol. 7; no. 1; p. 10993
• Main Authors: Hyun, Jeongeun, Wang, Sihyung, Kim, Jieun, Rao, Kummara Madhusudana, Park, Soo Yong, Chung, Ildoo, Ha, Chang-Sik, Kim, Sang-Woo, Yun, Yang H., Jung, Youngmi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-03-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/51; 13/89; 14/19; 14/35; 14/63; 38/35; 38/61; 38/89; 42/89; 631/337/384/331; 631/80/86; 64/60; 692/4020/4021/1607/1605; 692/4020/4021/288/2140; 82/29; 82/51; 96/1; 96/109; 96/63; Animals; Base Sequence; Carbon Tetrachloride; Carcinoma, Hepatocellular - genetics; Choline; Chronic Disease; Down-Regulation; Ethionine; Gene Expression Regulation; Hepatic Stellate Cells - metabolism; Humanities and Social Sciences; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Male; Methionine; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Sequence Data; multidisciplinary; Nanoparticles - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Protein Binding - genetics; Receptors, G-Protein-Coupled - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Smoothened Receptor; Transcription Factor RelA - metabolism; Zinc Finger Protein Gli2; Zinc Finger Protein Gli3
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10993

Hedgehog (Hh) signalling regulates hepatic fibrogenesis. MicroRNAs (miRNAs) mediate various cellular processes; however, their role in liver fibrosis is unclear. Here we investigate regulation of miRNAs in chronically damaged fibrotic liver. MiRNA profiling shows that expression of miR-378 family members (miR-378a-3p, miR-378b and miR-378d) declines in carbon tetrachloride (CCl
4
)-treated compared with corn-oil-treated mice. Overexpression of miR-378a-3p, directly targeting Gli3 in activated hepatic stellate cells (HSCs), reduces expression of Gli3 and profibrotic genes but induces
gfap
, the inactivation marker of HSCs, in CCl
4
-treated liver. Smo blocks transcriptional expression of miR-378a-3p by activating the p65 subunit of nuclear factor-κB (NF-κB). The hepatic level of miR-378a-3p is inversely correlated with the expression of Gli3 in tumour and non-tumour tissues in human hepatocellular carcinoma. Our results demonstrate that miR-378a-3p suppresses activation of HSCs by targeting Gli3 and its expression is regulated by Smo-dependent NF-κB signalling, suggesting miR-378a-3p has therapeutic potential for liver fibrosis.
Liver fibrosis is a pathogenic driver of many liver diseases, so understanding its regulation might open the door to new therapies. Here the authors perform a screen for miRNA candidates and identify that miR-378 inhibits liver fibrosis in mice by interfering with Hedgehog signalling in hepatic stellate cells.