Abstract
Oxidative stress induces the activation of liver fibrogenic cells (myofibroblasts), thus promoting the expression of fibrosis-related genes, leading to hepatic fibrogenesis. MicroRNAs (miRNAs) are a new class of small RNAs ~18–25 nucleotides in length involved in post-transcriptional regulation of gene expression. Wound-healing and remodeling processes in liver fibrosis have been associated with changes in hepatic miRNA expression. However, the role of miR-706 in liver fibrogenesis is currently unknown. In the present study, we show that miR-706 is abundantly expressed in hepatocytes. Moreover, oxidative stress leads to a significant downregulation of miR-706, and the further reintroduction of miR-706 inhibits oxidative stress-induced expression of fibrosis-related markers such as α-SMA. Subsequent studies revealed that miR-706 directly inhibits PKCα and TAOK1 expression via binding to the 3′-untranslated region, preventing epithelial mesenchymal transition. In vivo studies showed that intravenous injection of miR-706 agomir successfully increases hepatic miR-706 and decreases α-SMA, PKCα, and TAOK1 protein levels in livers of carbon tetrachloride (CCl4)-treated mice. In summary, this study reveals a protective role for miR-706 by blocking the oxidative stress-induced activation of PKCα/TAOK1. Our results further identify a major implication for miR-706 in preventing hepatic fibrogenesis and suggest that miR-706 may be a suitable molecular target for anti-fibrosis therapy.
Highlights
Chronic liver insults, such as viral hepatitis, metabolic or toxic diseases, autoimmune diseases, and non-alcoholic steatohepatitis, lead to the excessive deposition of extracellular matrix (ECM) and to the destruction of hepatic cells’ structure and function, resulting in the development of liver fibrosis[1,2]
To identify miRNAs involved in hepatic fibrogenesis, we applied a widely-used model of periportal fibrosis using CCl4 treatment, characterized by the excessive deposition of ECM, the reconstruction of hepatic lobules and loss of liver function (Supporting Fig. 1A–C)
Consistent with previous studies[22,23], the miR-29 and miR-122 families associated with gene encoding for ECM protein and collagen in fibrotic livers were downregulated in our analysis
Summary
Chronic liver insults, such as viral hepatitis, metabolic or toxic diseases, autoimmune diseases, and non-alcoholic steatohepatitis, lead to the excessive deposition of extracellular matrix (ECM) and to the destruction of hepatic cells’ structure and function, resulting in the development of liver fibrosis[1,2]. The activation and proliferation of fibroblasts plays a crucial role in hepatic fibrogenesis. Hepatic stellate cells (HSCs) are the major source of activated fibroblasts[4,5]. MiR-21 activates EMT via the PTEN/AKT pathway[11] and downregulation of miR-101 promotes hepatocyte EMT12,13. MiRNAs play fundamental physiological roles in a variety of biological processes, including cell proliferation, differentiation, metabolism, immune response, and apoptosis[16]. MiR-706 has been related to fatty-acid-regulated insulin resistance in mouse myoblasts[24], and to vesicular stomatitis virus-induced apoptosis by reducing the activation of caspase-3 and caspase-925. The levels of miR-706 were found to be significantly downregulated in CCl4-induced fibrotic livers. We further investigated the molecular mechanisms of miR-706 in liver fibrosis using bioinformatics indicating that PKCαand TAOK1 might be targeted genes regulated by miR-706
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