title: Class II HDAC inhibition hampers hepatic stellate cell activation by induction of microRNA-29.
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.
  
  
  OBJECTIVE
  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.
authors: Department of Cell Biology, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Inge
authors: I
authors: Mannaerts
authors: Nathalie
authors: N
authors: Eysackers
authors: Oscar O
authors: OO
authors: Onyema
authors: Katrien
authors: K
authors: Van Beneden
authors: Sergio
authors: S
authors: Valente
authors: Antonello
authors: A
authors: Mai
authors: Margarete
authors: M
authors: Odenthal
authors: Leo A
authors: LA
authors: van Grunsven
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D034622:RNA Interference
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C577554:MC1568; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D011758:Pyrroles; D002251:Carbon Tetrachloride; D006655:Histone Deacetylases
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