Alterations in Bile Acid Physiology in Wilson Disease

Background & Aims: Wilson disease (WD) is an autosomal recessive disorder that results in excessive hepatic copper causing hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver failure. Previous studies have revealed dysregulation of many FXR metabolic target genes in animal models of WD, including Bsep, the major determinant of bile flow. Approach & Results: We tested the hypothesis that the FXR-cistrome is decreased in Atp7b-/- mice in accord with dysregulated bile acid homeostasis. RNA-Seq and ChIP-Seq analyses of Atp7b-/- and wild-type (WT) mouse livers confirmed that significantly altered transcripts and FXR-binding events overlapped. Decreased FXR occupancy in Atp7b-/- versus WT mice was observed genes of metabolic pathways and bile acid homeostasis, while enrichment of FXR binding was observed pathways associated with cellular damage, such as the focal adhesion pathway. Consistent with decreased FXR function, serum and liver bile acid concentrations were higher in Atp7b-/- mice than in WT mice. Comparison of bile acid profiles in the serum of WD patients with “liver,” “neurological,” or “mixed” disease vs. healthy controls also revealed increases in specific bile acids in WD-liver vs. healthy controls. Conclusions: Atp7b-/- mice and WD patients exhibited changes in serum bile acid speciation, likely due to FXR dysfunction. These findings provide new insights into possible aberrant bile acid homeostasis in patients with WD. Overall design: We performed RNA-Sequencing in 6 month old wild-type and Atp7b KO mice. The fold change of gene change in WT vs. Atp7b KO was calculated.