title: miR-150 Deficiency Protects against FAS-Induced Acute Liver Injury in Mice through Regulation of AKT.
abstract: Although miR-150 is implicated in the regulation of immune cell differentiation and activation, it remains unknown whether miR-150 is involved in liver biology and disease. This study was performed to explore the potential role of miR-150 in LPS/D-GalN and Fas-induced liver injuries by using wild type and miR-150 knockout (KO) mice. Whereas knockout of miR-150 did not significantly alter LPS/D-GalN-induced animal death and liver injury, it protected against Fas-induced liver injury and mortality. The Jo2-induced increase in serum transaminases, apoptotic hepatocytes, PARP cleavage, as well as caspase-3/7, caspase-8, and caspase-9 activities were significantly attenuated in miR-150 KO mice. The liver tissues from Jo2-treated miR-150 KO mice expressed higher levels of Akt1, Akt2, total Akt, as well as p-Akt(Ser473) compared to the wild type livers. Pretreatment with the Akt inhibitor V reversed Jo2-induced liver injury in miR-150 KO mice. The primary hepatocytes isolated from miR-150 KO mice also showed protection against Fas-induced apoptosis in vitro (characterized by less prominent PARP cleavage, less nuclear fragmentation and less caspase activation) in comparison to hepatocytes from wild type mice. Luciferase reporter assays in hepatocytes transfected with the Akt1 or Akt2 3'-UTR reporter constructs (with or without mutation of miR-150 binding site) established Akt1 and Akt2 as direct targets of miR-150. Tail vein injection of lentiviral particles containing pre-miR-150 enhanced Jo2-induced liver injury in miR-150 KO mice. These findings demonstrate that miR-150 deficiency prevents Fas-induced hepatocyte apoptosis and liver injury through regulation of the Akt pathway.
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America.
authors.forename: Weina
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America.
authors.forename: Chang
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America.
authors.forename: Jinqiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America.
authors.forename: Kyoungsub
authors.initials: K
authors.lastname: Song
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America; Department of Gastroenterology and Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America.
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D019295:Computational Biology; D004791:Enzyme Inhibitors / Q000737:chemistry; D005688:Galactosamine / Q000737:chemistry; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000637:Transaminases / Q000097:blood; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C491899:Fas protein, mouse; D008070:Lipopolysaccharides; D035683:MicroRNAs; C529101:Mirn150 microRNA, mouse; D019014:fas Receptor; D005688:Galactosamine; D000637:Transaminases; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D020169:Caspases