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Acute Alcohol Exposure‐Induced let‐7a Inhibition Exacerbates Hepatic Apoptosis by Regulating Caspase‐3 in Mice
Author(s) -
Beane Kaleigh,
Pan Jeong Hoon,
Kim Hyunjin,
Tang Jingsi,
Park JeenWoo,
Kong Byungwhi C,
Shin EuiCheol,
Lee Jin Hyup,
Kim Jae Kyeom
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.582.8
Subject(s) - apoptosis , microrna , pathogenesis , tunel assay , mir 122 , transfection , alcohol , in vitro , downregulation and upregulation , messenger rna , gene expression , medicine , chemistry , cancer research , endocrinology , biology , gene , biochemistry
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 poorly understood. In this study, we aimed to explore effects of dysregulated miRNA profile on ALD conditions in mice. C57BL/6J male mice were treated with either saline (CON; oral gavage; n=8) or alcohol (EtOH; 3 g/kg·body weight; oral gavage; n=8) for 7 days. The ALD conditions were assessed by a serum AST/ALT ratio and hepatic fat accumulation. A total of 599 miRNA, and 158 key mRNAs of fatty liver and hepatotoxicity pathway were measured in liver tissues using NanoString miRNA expression array and quantitative real‐time PCR arrays, respectively. The array datasets were utilized to predict interactions with miRNAs. The predicted interactions of miRNA‐mRNA pairs were further validated using in vitro miRNA transfection experiments using AML12 mice hepatocytes. As results, miR‐21 and let‐7a were significantly decreased in EtOH group, and Ccng1 , Rb1 , and Casp3 mRNAs were predicted as their target genes. In addition, p53 expression was increased in the EtOH group, which is consistent with increased Casp3 activity, cPARP expression, and TUNEL positive cells by alcohol treatment. Similarly, in vitro suppression of let‐7a increased apoptosis by upregulating Cas‐3 protein expression in AML12 hepatocytes. Although there was no direct interaction between let‐7a and Rb1 protein expression, MDM2/p53 axis was also influenced by let‐7a inhibition. Therefore, alcohol‐induced inhibition of let‐7a may increase hepatic apoptosis by both directly targeting Casp3 , and indirectly modulating MDM2/p53 axis. Support or Funding Information This work was supported by the University of Arkansas, VPRED Start‐up fund (JKK, and JHP). Support has been provided in part by the Arkansas Biosciences Institute, a partnership of scientists from Arkansas Children's Hospital, Arkansas State University, the University of Arkansas‐Division of Agriculture, the University of Arkansas, Fayetteville, and the University of Arkansas for Medical Sciences. The Arkansas Biosciences Institute is the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000 (JKK, JHP, KEB, and BCK). This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF‐2015R1C1A1A01053746; JHL) as well as the China Scholarship Council (JT). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .