Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice

• Published in: Laboratory investigation Vol. 96; no. 12; pp. 1256 - 1267
• Main Authors: Kennedy, Lindsey L, Meng, Fanyin, Venter, Julie K, Zhou, Tianhao, Karstens, Walker A, Hargrove, Laura A, Wu, Nan, Kyritsi, Konstantina, Greene, John, Invernizzi, Pietro, Bernuzzi, Francesca, Glaser, Shannon S, Francis, Heather L, Alpini, Gianfranco
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.12.2016; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13/1; 13/2; 13/51; 14/19; 14/34; 14/63; 38/77; 631/337/384/331; 631/80/86; 64/60; 96/106; Animals; Apoptosis; Bile Ducts, Intrahepatic - metabolism; Bile Ducts, Intrahepatic - pathology; Biomarkers - metabolism; Cell Line; Cell Proliferation; Cells, Cultured; Cholestasis, Intrahepatic - metabolism; Cholestasis, Intrahepatic - pathology; Cholestasis, Intrahepatic - physiopathology; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Humans; Hyperplasia; Laboratory Medicine; Liver Cirrhosis - etiology; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; MicroRNAs - antagonists & inhibitors; MicroRNAs - biosynthesis; MicroRNAs - metabolism; Pathology; research-article; RNA Interference; Smad7 Protein - genetics; Smad7 Protein - metabolism; Up-Regulation
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2016.112

Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to have a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis. Wild-type (WT) and miR-21−/− mice underwent Sham or bile duct ligation (BDL) for 1 week, before evaluating liver histology, biliary proliferation, hepatic stellate cell (HSC) activation, fibrotic response, and small mothers against decapentaplegic 7 (Smad-7) expression. Invitro, immortalized murine biliary cell lines (IMCLs) and human hepatic stellate cell line (hHSC) were treated with either miR-21 inhibitor or control before analyzing proliferation, apoptosis, and fibrotic responses. In vivo, the levels of miR-21 were increased in total liver and cholangiocytes after BDL, and loss of miR-21 decreased the amount of BDL-induced biliary proliferation and intrahepatic biliary mass. In addition, loss of miR-21 decreased BDL-induced HSC activation, collagen deposition, and expression of the fibrotic markers transforming growth factor-β1 and α-smooth muscle actin. In vitro, IMCL and hHSCs treated with miR-21 inhibitor displayed decreased proliferation and expression of fibrotic markers and enhanced apoptosis when compared with control treated cells. Furthermore, mice lacking miR-21 show increased Smad-7 expression, which may be driving the decrease in biliary hyperplasia and hepatic fibrosis. During cholestatic injury, miR-21 is increased and leads to increased biliary proliferation and hepatic fibrosis. Local modulation of miR-21 may be a therapeutic option for patients with cholestasis.