Class II HDAC Inhibition Hampers Hepatic Stellate Cell Activation by Induction of MicroRNA-29

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Abstract

Background: The conversion of a quiescent vitamin A storing hepatic stellate cell (HSC) to a matrix producing, contractile myofibroblast-like activated HSC is a key event in the onset of liver disease following injury of any aetiology. Previous studies have shown that class I histone deacetylases (HDACs) are involved in the phenotypical changes occurring during stellate cell activation in liver and pancreas. Aims: In the current study we investigate the role of class II HDACs during HSC activation. Methods: We characterized the expression of the class II HDACs freshly isolated mouse HSCs. We inhibited HDAC activity by selective pharmacological inhibition with MC1568, and by repressing class II HDAC gene expression using specific siRNAs. Results: Inhibition of HDAC activity leads to a strong reduction of HSC activation markers α-SMA, lysyl oxidase and collagens as well as an inhibition of cell proliferation. Knock down experiments showed that HDAC4 contributes to HSC activation by regulating lysyl oxidase expression. In addition, we observed a strong up regulation of miR-29, a well-known anti-fibrotic miR, upon treatment with MC1568. Our in vivo work suggests that a successful inhibition of class II HDACs could be promising for development of future anti-fibrotic compounds. Conclusions: In conclusion, the use of MC1568 has enabled us to identify a role for class II HDACs regulating miR-29 during HSC activation. © 2013 Mannaerts et al.

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Mannaerts, I., Eysackers, N., Onyema, O. O., van Beneden, K., Valente, S., Mai, A., … van Grunsven, L. A. (2013). Class II HDAC Inhibition Hampers Hepatic Stellate Cell Activation by Induction of MicroRNA-29. PLoS ONE, 8(1). https://doi.org/10.1371/journal.pone.0055786

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