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Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis. PLoS One 2016;11(12):e0167435

Date

12/10/2016

Pubmed ID

27935974

Pubmed Central ID

PMC5147893

DOI

10.1371/journal.pone.0167435

Scopus ID

2-s2.0-85006001499 (requires institutional sign-in at Scopus site)   37 Citations

Abstract

Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury.

Author List

Arffa ML, Zapf MA, Kothari AN, Chang V, Gupta GN, Ding X, Al-Gayyar MM, Syn W, Elsherbiny NM, Kuo PC, Mi Z

Author

Anai N. Kothari MD Assistant Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antioxidants
Catechin
Cell Line
Hep G2 Cells
Hepatic Stellate Cells
Humans
Liver Cirrhosis
Male
MicroRNAs
Osteopontin
Rats, Sprague-Dawley
Tea
Up-Regulation