Chronic administration of valproic acid inhibits complete activation of mouse hepatic stellate cells in vitro and in vivo

Inge Mannaerts, Nele Nuytten, Albert Geerts, Leonardus Van Grunsven

Research output: Contribution to journalMeeting abstract (Journal)

Abstract

Background: Transdifferentiation of hepatic stellate cells (HSC) to myofibroblastic cells (MF) is a central event in liver fibrogenesis. Understanding molecular mechanisms that underlie this cellular event provide pivotal insights into development of new therapeutic modalities for cirrhosis. Stellate cell activation by liver injury leads to a phenotypic transdifferentiation characterized by loss of vitamin A and extensive production of extracellular matrix. This process can be mimicked in vitro by culturing freshly isolated hepatic stellate cells. The use of the histone deacetylase inhibitor (HDAC-I) trichostatin A in these cultures has shown that histone deacetylases (HDACs) might play a role in the pathogenesis of liver fibrosis. Here we investigated the influence of the class I specific HDAC-I, Valproic acid (VPA), on the transdifferentiation from quiescent to activated HSCs in vitro and in vivo.
Methods: Cultured HSCs were exposed to VPA. Cell proliferation was assessed by EdU incorporation assay. Histone acetylation was studied by immunocytochemistry. RNA levels were evaluated by RT-qPCR. Carbon tetrachloride intoxication was used to obtain in vivo HSC activation.
Results: The overall extend of septa formation in livers stained by Sirius Red was smaller in the VPA drinking animals compared to control animals. RNA analysis of the livers showed that VPA co-treatment inhibits the CCl4-induced upregulation of the classical profibrogenic markers ?SMA, Col1a1, TIMP-1 and MMP13. In vitro treatment of HSCs with VPA enhances histone H4 acetylation. It also strongly inhibits cell proliferation and the expression of HSC activation markers ?-SMA, Lox, Spp1 and Myh11. To specifically study the in vivo effect of VPA on HSC transdifferentiation, stellate cells were isolated from mice treated with CCl4 or CCl4+0.5% VPA for 2 weeks. Stellate cells isolated from VPA treated mice display lower RNA levels of activation markers ?-SMA, Lox and Spp1 compared to cells isolated from CCl4 treated mice.
Conclusions: Together, these results suggest that VPA hampers in vitro and in vivo HSC activation. The mechanism of VPA action is still under investigation, since an siRNA mediated knock-down of the class I HDACs could not completely mimic the effect of VPA on in vitro HSC activation.
Original languageEnglish
JournalActa Gastro-Enterologica Belgica
Volume72
Issue numberFasc. 1
Publication statusPublished - 2009
EventFinds and Results from the Swedish Cyprus Expedition: A Gender Perspective at the Medelhavsmuseet - Stockholm, Sweden
Duration: 21 Sep 200925 Sep 2009

Keywords

  • fibrosis
  • liver
  • stellate cells
  • valproic acid

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