Identification of high-copper-responsive target pathways in Atp7b knockout mouse liver by GSEA on microarray data sets.

The mutation of the Wilson's disease protein ATP7B has been widely used to study the direct link between hepatic high copper and development of liver pathology. Several studies have used gene expression profiling of high-copper effects to identify the key genes in the process, but few focused on the involved pathways and the coexpression patterns of associated pathways. We used a microarray data set from the public database library of GEO (Gene Expression Omnibus), which is associated with liver transcriptome in the early stages of copper accumulation in the mouse model of Wilson's disease under Atp7b knockout. To be more powerful than conventional single-gene methods in the study of complex diseases, we applied gene set enrichment analysis (GSEA) on the data sets and performed candidate transcription factors selection. As a result, 16 upregulated pathways such as tryptophan metabolism and cell cycle and 15 downregulated pathways such as TCA cycle and PPAR signaling pathway were identified as high-copper-responsive target pathways in Atp7b knockout mouse liver, and most of them had not been reported on previously. Finally, coexpression networks of related pathways were constructed with the significant core genes and transcription factors such as SREBP1 and PPARG. The results of our study may help us better understand the molecular mechanisms of high-copper effects in mice liver in genome-wide.