Department of Cell Biology, Vrije Universiteit Brussel, Brussels, Belgium.
Hepatology. 2010 Feb;51(2):603-14. doi: 10.1002/hep.23334.
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.
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.
肝星状细胞（HSC）的激活是肝纤维化发病机制中的关键步骤。因此，阐明这种转分化过程对于开发有效的纤维化治疗方法非常重要。我们分析了组蛋白去乙酰化酶抑制剂丙戊酸（VPA）对体外和体内小鼠 HSC 转分化的影响。将 2.5mM 的 VPA 暴露于新鲜分离的小鼠 HSCs 中会导致组蛋白 H4 乙酰化增加并抑制细胞增殖。通过定量聚合酶链反应和 Western blot 分析的星状细胞激活标志物的表达表明，VPA 处理抑制了激活标志物如 Acta2、Lox、Spp1 和 Myh11 的诱导。VPA 处理可减少 CCl4 处理小鼠肝脏中的胶原沉积和体内星状细胞的激活。通过 RNA 干扰沉默小鼠 HSCs 中的 I 类组蛋白脱乙酰酶仅部分模拟了 VPA 的处理。
VPA 的慢性给药导致体外和体内星状细胞激活明显减少。我们假设 VPA 的作用部分来自 I 类组蛋白脱乙酰酶抑制，但也涉及非组蛋白脱乙酰酶 I 类 VPA 靶标参与星状细胞激活过程。
