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.
Highlights
Hepatic fibrosis is the wound-healing response that results from chronic liver injury [1, 2]
A review of the miRBase Target Database (Available online: http://www.mirbase.org/) showed that these three miRNAs target OPN mRNA. In this current study we demonstrated that hepatocyte-derived OPN expression induces hepatic stellate cells (HSCs) into an activated state and investigated whether miRNAs mediate EGCG-dependent OPN mRNA decay using both in vitro and in vivo toxin-induced liver injury and fibrosis models
HSCs and we elucidated a novel mechanism in which EGCG modulated miRNA expression to target OPN mRNA for degradation and subsequently prevented hepatic fibrosis
Summary
Hepatic fibrosis is the wound-healing response that results from chronic liver injury [1, 2]. The resulting development of nodules of regenerating hepatocytes, PLOS ONE | DOI:10.1371/journal.pone.0167435. EGCG Upregulates miR-221 to Inhibit Hepatic Fibrosis leads to cirrhosis. Cirrhosis is characterized by hepatocellular dysfunction, increased resistance to blood flow, and subsequent portal hypertension, a fatal sequela [3]. Liver cirrhosis is estimated to be the 12th leading cause of death in the world; accounting for 1.021 million deaths based on WHO global estimates, and current treatment options are limited. Current research seeks to develop alternative therapies and identify new molecular targets
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