title: Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl-1.
abstract: Fas-induced apoptosis is involved in diverse liver diseases. Herein, we investigated the effect of Mir155 deletion on Fas-induced liver injury. Wild-type (WT) mice and Mir155 knockout (KO) mice were i.p. administered with the anti-Fas antibody (Jo2) to determine animal survival and the extent of liver injury. After Jo2 injection, the Mir155 KO mice exhibited prolonged survival versus the WT mice (P < 0.01). The Mir155 KO mice showed lower alanine aminotransferase and aspartate aminotransferase levels, less liver tissue damage, fewer apoptotic hepatocytes, and lower liver tissue caspase 3/7, 8, and 9 activities compared with the WT mice, indicating that Mir155 deletion prevents Fas-induced hepatocyte apoptosis and liver injury. Hepatocytes isolated from Mir155 KO mice also showed resistance to Fas-induced apoptosis, in vitro. Higher protein level of myeloid cell leukemia-1 (Mcl-1) was also observed in Mir155 KO hepatocytes compared to WT hepatocytes. A miR-155 binding site was identified in the 3'-untranslated region of Mcl-1 mRNA; Mcl1 was identified as a direct target of miR-155 in hepatocytes. Consistently, pretreatment with a siRNA specific for Mcl1 reversed Mir155 deletion-mediated protection against Jo2-induced liver tissue damage. Finally, restoration of Mir155 expression in Mir155 KO mice abolished the protection against Fas-induced hepatocyte apoptosis. Taken together, these findings demonstrate that deletion of Mir155 prevents Fas-induced hepatocyte apoptosis and liver injury through the up-regulation of Mcl1.
authors: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
authors: Weina
authors: W
authors: Chen
authors: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
authors: Chang
authors: C
authors: Han
authors: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
authors: Jinqiang
authors: J
authors: Zhang
authors: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
authors: Kyoungsub
authors: K
authors: Song
authors: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana; Department of Gastroenterology and Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Ying
authors: Y
authors: Wang
authors: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana. Electronic address: twu@tulane.edu.
authors: Tong
authors: T
authors: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005688:Galactosamine; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D020011:Protective Agents; D019014:fas Receptor; D005688:Galactosamine; D020169:Caspases