Article ; Online: High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease-related fibrosis.
Translational research : the journal of laboratory and clinical medicine
2015 Volume 166, Issue 3, Page(s) 304–314
Abstract: ... disease (NAFLD). To identify miRNAs that mediate NAFLD-related fibrosis, we used high-throughput ... sequencing to assess miRNAs obtained from liver biopsies of 15 individuals without NAFLD fibrosis (F0) and 15 ... gene expression, may play a role in the regulation of metabolic disorders, including nonalcoholic fatty liver ...
| Abstract | Recent evidence suggests that microRNAs (miRNAs), small, noncoding RNA molecules that regulate gene expression, may play a role in the regulation of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). To identify miRNAs that mediate NAFLD-related fibrosis, we used high-throughput sequencing to assess miRNAs obtained from liver biopsies of 15 individuals without NAFLD fibrosis (F0) and 15 individuals with severe NAFLD fibrosis or cirrhosis (F3-F4), matched for age, sex, body mass index, type 2 diabetes status, hemoglobin A1c, and use of diabetes medications. We used DESeq2 and Kruskal-Wallis test to identify miRNAs that were differentially expressed between NAFLD patients with or without fibrosis, adjusting for multiple testing using Bonferroni correction. We identified a total of 75 miRNAs showing statistically significant evidence (adjusted P value <0.05) for differential expression between the 2 groups, including 30 upregulated and 45 downregulated miRNAs. Quantitative reverse-transcription polymerase chain reaction analysis of selected miRNAs identified by sequencing validated 9 of 11 of the top differentially expressed miRNAs. We performed functional enrichment analysis of dysregulated miRNAs and identified several potential gene targets related to NAFLD-related fibrosis including hepatic fibrosis, hepatic stellate cell activation, transforming growth factor beta signaling, and apoptosis signaling. We identified forkhead box O3 and F-box WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) as potential targets of miR-182, and found that levels of forkhead box O3, but not FBXW7, were significantly decreased in fibrotic samples. These findings support a role for hepatic miRNAs in the pathogenesis of NAFLD-related fibrosis and yield possible new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis. |
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| MeSH term(s) | Demography ; Down-Regulation/genetics ; Female ; Gene Expression Profiling ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Liver/metabolism ; Liver/pathology ; Liver Cirrhosis/complications ; Liver Cirrhosis/genetics ; Liver Cirrhosis/pathology ; Male ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Middle Aged ; Non-alcoholic Fatty Liver Disease/complications ; Non-alcoholic Fatty Liver Disease/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Real-Time Polymerase Chain Reaction ; Reproducibility of Results ; Up-Regulation/genetics | |||||
| Chemical Substances | MicroRNAs ; RNA, Messenger | |||||
| Language | English | |||||
| Publishing date | 2015-09 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural | |||||
| ZDB-ID | 2246684-8 | |||||
| ISSN | 1878-1810 ; 1532-6543 ; 1931-5244 | |||||
| ISSN (online) | 1878-1810 ; 1532-6543 | |||||
| ISSN | 1931-5244 | |||||
| DOI | 10.1016/j.trsl.2015.04.014 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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