title: Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice.
abstract: 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. In vitro, 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.
authors: Research, Central Texas Veterans Health Care System, Temple, TX, USA.|Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
authors: Lindsey L
authors: LL
authors: Kennedy
authors: Research, Central Texas Veterans Health Care System, Temple, TX, USA.|Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.|Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA.
authors: Fanyin
authors: F
authors: Meng
authors: Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
authors: Julie K
authors: JK
authors: Venter
authors: Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
authors: Tianhao
authors: T
authors: Zhou
authors: Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA.
authors: Walker A
authors: WA
authors: Karstens
authors: Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA.
authors: Laura A
authors: LA
authors: Hargrove
authors: Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
authors: Nan
authors: N
authors: Wu
authors: Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
authors: Konstantina
authors: K
authors: Kyritsi
authors: Operational Funds, Baylor Scott & White Health, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
authors: John
authors: J
authors: Greene
authors: Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Pietro
authors: P
authors: Invernizzi
authors: Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Francesca
authors: F
authors: Bernuzzi
authors: Research, Central Texas Veterans Health Care System, Temple, TX, USA.|Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.|Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA.
authors: Shannon S
authors: SS
authors: Glaser
authors: Research, Central Texas Veterans Health Care System, Temple, TX, USA.|Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.|Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA.
authors: Heather L
authors: HL
authors: Francis
authors: Research, Central Texas Veterans Health Care System, Temple, TX, USA.|Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.|Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA.|Operational Funds, Baylor Scott & White Health, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
authors: Gianfranco
authors: G
authors: Alpini
mesh_terms: D000818:Animals; D017209:Apoptosis; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D002780:Cholestasis, Intrahepatic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D008103:Liver Cirrhosis / Q000209:etiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D034622:RNA Interference; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D051906:Smad7 Protein