Friedman Scott L
Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
J Gastroenterol Hepatol. 2006 Oct;21 Suppl 3:S79-83. doi: 10.1111/j.1440-1746.2006.04585.x.
The identification of activated hepatic stellate cells and related cell types as key fibrogenic effectors during liver injury has led to intense evaluation of transcriptional events underlying their behavior. While initial studies focused on characterizing interactions between transcription factors and regulatory regions within gene promoters, epigenetic mechanisms have emerged as major determinants of gene activation and repression, in particular histone acetylation and promoter methylation, as well as other complex conditional interactions that underlie global changes in gene expression. Three examples are provided that illustrate how stellate cell activation may be controlled by widely divergent regulatory pathways, including alternative splicing of a growth inhibitory transcription factor (Kruppel-like factor-6), epigenetic regulation of a factor regulating stellate cell survival (nuclear factor kappaB), and regulation of a transcription factor whose expression maintains stellate cell quiescence (LIM homeobox gene 2 [Lhx2]). These complex cascades illustrate how clarifying the finely tuned interdependent layers of transcriptional, translational, post-translational and epigenetic gene regulation in stellate cells is raising new prospects for therapy of hepatic fibrosis.
肝星状细胞及相关细胞类型被鉴定为肝损伤期间关键的致纤维化效应细胞，这引发了对其行为背后转录事件的深入评估。虽然最初的研究集中于表征转录因子与基因启动子内调控区域之间的相互作用，但表观遗传机制已成为基因激活和抑制的主要决定因素，特别是组蛋白乙酰化和启动子甲基化，以及构成基因表达全局变化基础的其他复杂条件性相互作用。本文提供了三个例子，说明肝星状细胞激活如何受广泛不同的调控途径控制，包括生长抑制转录因子（Kruppel样因子6）的可变剪接、调节星状细胞存活的因子（核因子κB）的表观遗传调控，以及其表达维持星状细胞静止的转录因子（LIM同源盒基因2 [Lhx2]）的调控。这些复杂的级联反应表明，阐明星状细胞中转录、翻译、翻译后和表观遗传基因调控的精细调节的相互依赖层次，为肝纤维化治疗带来了新的前景。
