Identification of hepatic genes regulated in early phase of cholestasis by cDNA microarray analysis in rats

胆汁淤积是主要的肝脏疾病之一，可导致进行性肝纤维化和肝硬化。鉴定在胆汁淤积早期阶段改变的基因对于了解胆汁淤积进展的分子机制至关重要。在这项研究中，我们通过cDNA微阵列分析研究了肝脏对已建立的啮齿动物胆汁淤积模型（胆总管结扎和α- naphtylisothieyanate中毒模型）的转录反应的时间模式，以确定在胆汁淤积中特异性调节的基因，无论刺激治疗如何。通过对多个时间点数据的聚类分析，我们确定了25个基因在胆汁淤积症的早期阶段对两种治疗表现出相似的转录反应。这些基因包括一个小的异二聚体伴侣及其靶基因，这些基因被认为是参与细胞保护机制的基因，以防止累积的有毒胆汁酸。鉴定的基因还包括参与细胞凋亡和组织再生的基因，这些基因可能与细胞保护和修复细胞损伤事件的机制有关。所鉴定的基因还包括参与碳酸氢盐和谷胱甘肽合成和分泌的基因，这些基因的下调可能解释了胆汁淤积症中胆汁流量减少的原因。总之，我们通过cDNA微阵列分析确定了25个在绿藻停滞早期特异性调控的基因。多种胆汁淤积模型的微阵列分析结合多时间点数据的聚类分析似乎是一种有效的方法，用于识别普遍存在于胆汁淤积早期阶段的基因及其分子途径。

Cholestasis is one of the major liver diseases and results in the progressive liver fibrosis and cirrhosis. Identification of genes altered in the early phase of cholestasis is essential to understand the molecular mechanisms of the progression of cholestasis. In this study, we examined the temporal patterns of transcriptional response of the liver to established rodent models of cholestasis (common bile duct ligation and α-naphtylisothioeyanate intoxication models) by cDNA microarray analysis to identify genes specifically regulated in cholestasis regardless of the stimulating treatment. By clustering analysis of multiple time-point data, we identified 25 genes showing similar transcriptional responses to both of the treatments in the early phase of cholestasis. These genes included a small heterodimer partner and its target genes that have been regarded as genes involved in mechanisms of cell protection against accumulated toxic bile acids. The genes identified also included genes involved in apoptosis and tissue regeneration that may be related to the mechanisms of cytoprotection against and to repair events of cell injury. The identified genes also included genes involved in the synthesis and secretion of bicarbonate and glutathione, and down-regulation of these genes may explain decreased bile flow in cholestasis. In conclusion, we identified 25 genes specifically regulated in the early phase of chloestasis by cDNA microarray analysis. Microarray analysis of multiple models of cholestasis coupled with clustering analysis of multiple time-point data appears to be a useful approach for identifying genes and their molecular pathways that universally exist in the early phase of cholestasis.