Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cells in vitro and in vivo.
Hepatic stellate cell (HSC) activation is a pivotal step in the pathogenesis of liver fibrosis. The clarification of this transdifferentiation process is therefore important for the development of effective therapies for fibrosis. We analyzed the effect of a histone deacetylase inhibitor, valproic acid (VPA), on mouse HSC transdifferentiation in vitro and in vivo. The exposure of freshly isolated mouse HSCs to 2.5 mM VPA led to increased histone H4 acetylation and inhibited cell proliferation. Expression of stellate cell activation markers analyzed by quantitative polymerase chain reaction and western blotting revealed that treatment with VPA inhibited the induction of activation markers such as Acta2, Lox, Spp1, and Myh11. Treatment of mice with VPA decreased collagen deposition and in vivo activation of stellate cells in the livers of CCl(4)-treated mice. Class I histone deacetylase silencing through RNA interference in mouse HSCs only partially mimicked treatment with VPA.


CONCLUSIONS
Chronic administration of VPA results in a marked decrease in stellate cell activation both in vitro and in vivo. We hypothesize that the VPA effect results partially from class I histone deacetylase inhibition, but that also non-histone deacetylase class I VPA targets are involved in the stellate cell activation process.
Mannaerts
Inge
I
Department of Cell Biology, Vrije Universiteit Brussel, Brussels, Belgium.
Nuytten
Nele R
NR
Rogiers
Vera
V
Vanderkerken
Karin
K
van Grunsven
Leo A
LA
Geerts
Albert
A
D000818:Animals; D054338:Cell Transdifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014635:Valproic Acid / Q000008:administration & dosage* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D014635:Valproic Acid; D056284:Histone Deacetylase 1