Transcriptional reprogramming in murine liver defines the physiologic consequences of biliary obstruction

Background/Aims: While the metabolic and histological responses to cholestasis are recognized, the consequences of impaired biliary flow on liver gene expression are largely undefined. We hypothesized that biliary obstruction results in transcriptional reprogramming that dictates the physiologic response. Methods: We determined global gene expression in murine livers 1-21 days following bile duct ligation. Total hepatic cRNA from experimental and sham mice was hybridized to Affymetrix gene chips. Gene expression data was analyzed by GeneSpring® software and validated by Northern analysis. Results: We found 92 genes over-expressed ≥2-fold at one or more time points following bile duct ligation. Functional classification of these genes revealed the activation of three main biological processes in a sequential and time-restricted fashion. At day 1, genes involved in sterol metabolism were uniquely over-expressed, including HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. This was followed by an increased expression of growth-promoting genes at day 7, the time point coinciding with peak cholangiocyte proliferation. In later phases (days 14-21), the liver over-expressed genes encoding structural proteins and proteases. Conclusions: Transcriptional reprogramming in the liver following biliary obstruction favors the activation of genes regulating metabolism, cell proliferation, and matrix remodeling in a time-restricted and sequential fashion.