title: miR-15b and miR-16 regulate TNF mediated hepatocyte apoptosis via BCL2 in acute liver failure.
abstract: Acute liver failure (ALF) still has an unacceptable high mortality rate, despite substantial improvements with multidisciplinary care. The precise underlying mechanism of ALF remains to be explored. It has been reported that microRNAs (miRNAs) are novel regulators in a number of liver diseases, but the role of miRNAs in the development of ALF is not fully understood. An ALF murine model was generated by ip injection of D: -GalN/LPS, which was confirmed with histopathology and biochemistry. The hepatic miRNA expression profile in ALF was determined by microarray and verified by qRT-PCR. The functions and signal pathways of the targeted genes of these deregulated miRNAs were predicted, using bioinformatics analysis. The possible underlying mechanism was investigated by exploring the relationship between miRNA modification and hepatocyte apoptosis. There were a total of 95 significantly changed miRNAs in ALF compared to mock-treated (P < 0.01). Among these 95 miRNAs, 20 were up-regulated and 26 were down-regulated at both 5 and 7 h time points. Bioinformatics analysis predicted that some of these 46 miRNAs were involved in apoptosis. Among the up-regulated miRNAs involved in apoptosis, miR-15b and miR-16 showed the highest enrichment and targeted the common anti-apoptotic gene, BCL2. Our in vitro data demonstrated that miR-15b and/or miR-16 regulated BCL2 at the protein level. Inhibition of miR-15b and/or miR-16 reduced hepatic apoptosis and TNF production. These data suggest that miR-15b and miR-16 regulate TNF mediated hepatic apoptosis via BCL2 during ALF, and may shed light on the development of a therapeutic strategy for treatment of ALF.
authors.affiliation: Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, People's Republic of China.
authors.forename: Fangmei
authors.initials: F
authors.lastname: An
authors.forename: Bangdong
authors.initials: B
authors.lastname: Gong
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Dongshan
authors.initials: D
authors.lastname: Yu
authors.forename: Gangde
authors.initials: G
authors.lastname: Zhao
authors.forename: Lanyi
authors.initials: L
authors.lastname: Lin
authors.forename: Weiliang
authors.initials: W
authors.lastname: Tang
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Shisan
authors.initials: S
authors.lastname: Bao
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D019295:Computational Biology; D015536:Down-Regulation / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D018836:Inflammation Mediators; D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse; C522604:Mirn16 microRNA, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha