Plasma miR-218a-5p as a biomarker for acute cholestatic liver injury in rats and investigation of its pathophysiological roles.
biomarker
cholangiocytes
cholestasis
circulating microRNA
drug-induced liver injury
microRNA target
Journal
Journal of applied toxicology : JAT
ISSN: 1099-1263
Titre abrégé: J Appl Toxicol
Pays: England
ID NLM: 8109495
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
28
12
2020
received:
04
10
2020
accepted:
11
01
2021
pubmed:
11
2
2021
medline:
8
2
2022
entrez:
10
2
2021
Statut:
ppublish
Résumé
MicroRNAs (miRNA) have received considerable attention as potential biomarkers for drug-induced liver injury. We recently reported that the plasma levels of miR-143-3p and miR-218a-5p increased in severe cholestasis in rats. This study aimed to investigate whether these miRNAs increase in a severity-dependent manner and to elucidate their pathophysiological roles in cholestasis. Male Sprague-Dawley rats were orally administered different doses of α-naphthylisothiocyanate or 4,4-methylenedianiline to induce acute cholestasis. They were also orally administered acetaminophen or thioacetamide to induce hepatocellular injury. We found that plasma miR-143-3p and miR-218a-5p levels increased in a dose-dependent manner in cholestatic rats but not in hepatocellular injury. Bioinformatic analysis provided putative target genes of hsa-miR-218-5p, rno-miR-218a-5p, and mmu-miR-218-5p, among which GNAI2, PPP1CB, and PPP2R5A were experimentally validated as their direct target genes in human cholangiocyte line MMNK-1. Proliferation of MMNK-1 cells was significantly suppressed after overexpression of miR-218-5p and transduction of siRNAs for GNAI2, PPP1CB, and PPP2R5A. In the cholestatic livers of rats, Ppp1cb and Ppp2r5a expression levels decreased, whereas Gnai2 expression levels increased compared with those in vehicle-treated rats, suggesting that Ppp1cb and Ppp2r5a may be under the control of miR-218a-5p in vivo. In conclusion, our data suggest that miR-218(a)-5p is involved in the suppression of cholangiocyte proliferation by inhibiting the expression of PPP1CB and PPP2R5A, thereby contributing to the pathogenesis of cholestasis; and miR-218a-5p leaks into the plasma probably from damaged cholangiocytes in a severity-dependent manner in rats. Therefore, miR-218a-5p overexpression could be one of the underlying mechanisms of acute cholestatic liver injury in rats.
Substances chimiques
Biomarkers
0
Isothiocyanates
0
MicroRNAs
0
Thioacetamide
075T165X8M
Acetaminophen
362O9ITL9D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1537-1552Informations de copyright
© 2021 John Wiley & Sons, Ltd.
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