Inactivation of Atp7b copper transporter in the intestinal epithelial cells is associated with altered lipid processing and cell growth machinery that are independent from hepatic copper accumulation and liver histology severity

The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and brain, but little is known about the role of other organs expressing the ATP7B copper transporter on the metabolic changes characterizing WD. To examine the metabolic and morphological consequences of intestine Atp7b inactivation in absence of hepatic copper accumulation, we generated a new mouse strain, the Atp7b?IEC mouse and characterized its phenotype over a time-course study. Atp7b?IEC mice were generated using B6.Cg-Tg(Vil1-cre)997Gum/J mice from the Jackson Laboratory and Atp7bLox/Lox mice. Cre-mediated removal of a 1.6-kb fragment in exon 2 results in enterocyte-specific Atp7b inactivation. Atp7b?IEC mice were compared to wildtype mice with same genetic background (iWT). The Atp7b null global knockout (Atp7b -/-) on a C57Bl/6 background was previously generated and compared to respective WT. Mice were studied at 9, 16, 24, and 30 weeks of age. Liver and intestine histology, lipid metabolism parameters, and hepatic copper quantification were assessed. Transcriptome analysis in Atp7b?IEC mice revealed changes in genes involved in AMPK signaling, fatty acid metabolism and cell cycle both in the intestinal epithelial cells and in the liver. No changes in hepatic and enterocyte copper levels were seen in Atp7b?IEC livers, whereas, as expected, hepatic copper was 20-40 times higher in Atp7b -/- mice compared to WT mice. Intestine-specific Atp7b deficit affects systemic metabolic pathways independently from hepatic copper accumulation indicating evidence that WD phenotype is affected by organ-specific ATP7B variants. Overall design: Comparative gene expression profiling analysis of RNA-seq data for global ATP7B and Intestine-specific ATP7B knock-out mice model with their respective control mice in intestinal epithelial cells and liver