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

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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.