Reply:

Authors

  • Inge Mannaerts M.S.,

    1. Liver Cell Biology Lab, Department of Cell Biology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
    Search for more papers by this author
  • Leo van Grunsven Ph.D.

    1. Liver Cell Biology Lab, Department of Cell Biology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
    Search for more papers by this author

  • Potential conflict of interest: Nothing to report.

Reply:

We thank Ikura et al. for their interest in our recently published article1 on the inhibitory effect of valproic acid (VPA) on hepatic stellate cell activation and consequent liver fibrosis in a chronically injured mouse liver.

We fully agree with their opinion that prudence concerning the use of VPA in a clinical context is required. Their concern that VPA leads to adverse side effects was addressed in all treated mice by histological examination, but no obvious steatosis was observed. In addition, serum aminotransferase levels were not influenced by VPA treatment, and this suggests no direct hepatotoxic effect during these relatively short treatments in mice, as described earlier by Xia et al.2 We certainly do not suggest the immediate use of VPA as a therapeutic option for liver fibrosis. The use of VPA in the CCl4-induced mouse model of fibrosis has enabled us to demonstrate that class I histone deacetylases (HDACs) are involved in the activation of hepatic stellate cells. Our article is the first step toward the identification of HDAC-containing repressor complexes that govern this activation process in hepatic stellate cells.

Because of their beneficial effects in several hematological and solid malignancies, several HDAC inhibitors are currently being evaluated in clinical trials.3 Those inhibitors that do not show adverse hepatic side effects could be tested for their capacity to inhibit liver fibrosis. Further research is most certainly needed to obtain reliable and specific delivery of HDAC inhibitors to hepatic stellate cells. A very promising approach using vitamin A–coupled liposomes was recently proposed.4

Inge Mannaerts M.S.*, Leo van Grunsven Ph.D.*, * Liver Cell Biology Lab, Department of Cell Biology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.

Ancillary