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Acute alcohol consumption-induced let-7a inhibition exacerbates hepatic apoptosis by regulating Rb1 in mice

Authors
Pan, Jeong HoonKim, HyunjinTang, JingsiBeane, Kaleigh E.Park, Jeen-WooKong, SeongbaeKong, Byungwhi C.Kim, Young JunShin, Eui-CheolKim, Jun HoZhao, JiangchaoLee, Jin HyupKim, Jae Kyeom
Issue Date
6월-2020
Publisher
ELSEVIER SCIENCE INC
Keywords
alcoholic liver injury; apoptosis; let-7a; Rb1
Citation
ALCOHOL, v.85, pp.13 - 20
Indexed
SCIE
SCOPUS
Journal Title
ALCOHOL
Volume
85
Start Page
13
End Page
20
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/55612
DOI
10.1016/j.alcohol.2019.10.008
ISSN
0741-8329
Abstract
Alcohol consumption is a critical risk factor for hepatic pathogenesis, including alcoholic liver diseases (ALD), but implications of alcohol-induced dysregulation of microRNA (miRNA) in ALD pathogenesis are not completely understood. In the present study, C57BL/6J male mice were treated with saline (CON; oral gavage; n = 8) or alcohol (EtOH; 3 g/kg body weight; oral gavage; n = 8) for 7 days. A total of 599 miRNAs and 158 key mRNAs related to fatty liver and hepatotoxicity pathways were assessed in mice liver tissues. The mRNA expression datasets were then utilized to predict interactions with miRNAs that were changed by alcohol consumption. Predicted miRNA-mRNA interactions were validated using in vitro miRNA transfection experiments. The results showed that let-7a was significantly decreased in the EtOH group and Rb1 mRNA was predicted as a target gene. This was further supported by an inverse correlation of RB1 and let-7a expression in mice liver tissue. Additionally, key protein expressions involved in RB1-apoptosis axis [i.e., p73, cleaved CASP-3 (cCASP-3), and cCASP-7] showed a trend of increase in the EtOH mice; this was also confirmed by capase-3 enzyme activity and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay in livers of mice that had consumed alcohol. In line with our in vivo observations, alcohol treatment suppressed the let-7a expression and subsequently upregulated p73, cCASP-3, and cCASP-7 protein expressions in mice hepatocytes. Additional proteins in the apoptosis regulatory pathway (i.e., MDM2-p53 axis) were significantly changed in response to let-7a suppression in the cells. Taken together, the current study provides mechanistic evidence that alcohol consumption-induced let-7a suppression results in the upregulation of RB1, thereby promoting hepatic apoptosis through induction of pro-apoptotic proteins (e.g., p73), and by, at least in part, preventing MDM2-mediated p53 degradation. (C) 2019 Elsevier Inc. All rights reserved.
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