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

Abstract

BackgroundThe 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.AimsIn the current study we investigate the role of class II HDACs during HSC activation.MethodsWe 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.ResultsInhibition 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.ConclusionsIn conclusion, the use of MC1568 has enabled us to identify a role for class II HDACs regulating miR-29 during HSC activation.

Relationship between Liver Pathology and Disease Progression in a Murine Model of Amyotrophic Lateral Sclerosis

“…In patients with ALS, the upregulation of HDAC4 in skeletal muscle is associated with muscle denervation [35]. Additionally, HDAC4 has been related to fibrosis [36]; Barbier-Torres et al [37] showed that HDAC4 expression promoted cholestatic liver injury and alleviated liver fibrosis in mice. Interestingly, PDGF signaling is also overactivated in fibrotic disease [38], and its inhibition attenuates experimental liver fibrogenesis [39].…”

Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis

“…For example, Class I HDACs such as HDAC1 and HDAC2 were easily detected in quiescent HSCs, their protein expression decreased during stellate cell activation, whereas HDAC8 is induced and HDAC3 seems to be expressed at constant levels [29]. Among Class II HDACs, HDAC4 was accumulated during HSCs trans-differentiation, however a significant down-regulation for HDAC9, 10 and constant expressions of HDAC5, 6 and 7 were observed [9,28].…”

“…Yet, more research is needed to draw an accurate, global picture of the functional roles for all HDAC isoforms in liver fibrosis. Inge Mannaerts and the co-workers indicated that inhibition of Class II HDACs leads to a noticeable reduction of HSC activation markers as well as an inhibition of cell proliferation [9]. Specifically speaking, knock down experiments shows that inhibiting HDAC4, 5 and 6 partially hinders HSC activation through induction of microRNA-29, a well-known anti-fibrotic micro RNA [9].…”

Decoding liver injury: A regulatory role for histone modifications

“…In further support of a role for class II HDACs in liver fibrosis, HDAC7 and HDAC4 have been found to aid HSC activation by directly repressing HGF and MMP genes, respectively (Pannem et al , 2014, Qin andHan, 2010). Of great interest, a specific class II HDAC inhibitor MC1568 was found to significantly down-regulate fibrogenic genes in cultured HSCs and ameliorate liver fibrosis in mice (Mannaerts, Eysackers, 2013).…”

“…Mannaerts et al conducted an expression profiling of class II HDACs in primary HSCs (Mannaerts et al , 2013). Although all known class II HDACs were expressed in HSCs, only HDAC6 and HDAC10 exhibited significant alterations during HSC activation.…”