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

胆汁淤积是一种主要的肝脏疾病，可导致进行性肝纤维化和肝硬化。识别胆汁淤积早期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，我们研究了转录反应的时间模式，建立啮齿动物模型的胆汁淤积（胆总管结扎和α-萘异硫代嘌呤中毒模型）的cDNA微阵列分析，以确定基因特异性调节胆汁淤积，无论刺激治疗。通过对多个时间点数据的聚类分析，我们确定了25个基因，这些基因在胆汁淤积的早期阶段对两种治疗显示出相似的转录反应。这些基因包括一个小的异源二聚体伴侣和它的靶基因，这些基因被认为是参与细胞保护机制的基因。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损伤的细胞保护机制和修复事件有关。已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胆汁淤积时胆汁流量减少。总之，我们通过cDNA微阵列分析确定了25个在前列腺增生早期特异性调控的基因。多个模型的胆汁淤积加上聚类分析的多个时间点的数据的微阵列分析似乎是一个有用的方法，用于识别普遍存在于早期胆汁淤积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.