PuSH - Publikationsserver des Helmholtz Zentrums München

Cáceres, A.* ; Shibata, N.M.* ; Davalos-Gutierrez, C.D.* ; Sarode, G.V.* ; Hussan, H.* ; Bettencourt, M.* ; Fontes, A. ; Zischka, H. ; Lutsenko, S.* ; Heffern, M.C.* ; Medici, V.*

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

Am. J. Pathol., DOI: 10.1016/j.ajpath.2025.09.015 (2025)
Postprint Forschungsdaten DOI PMC
Open Access Green
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 metabolic and ultrastructural changes characterizing WD. To examine the consequences of intestinal Atp7b inactivation in the absence of hepatic copper accumulation, a new mouse model (Atp7bΔIEC) characterized by enterocyte-specific Atp7b inactivation was generated. Atp7bΔIEC mice were compared to wildtype mice with the same genetic background (iWT). The Atp7b global knockout (Atp7b-/-) model of WD on a C57Bl/6 background was previously generated and compared to respective WT. Hepatic copper, lipid metabolism, liver and intestine histology and electron microscopy were assessed over time up to 30 weeks of age. Whereas there was no evidence of intestine copper accumulation in the Atp7bΔIEC mice, transcriptome analysis in Atp7bΔIEC mice revealed changes in genes involved in AMPK signaling, fatty acid metabolism, and cell cycle both with partial overlap between the intestinal epithelial cells and the liver. Mitochondrial and other ultrastructural changes were observed in the intestinal epithelial cells of both Atp7b-/- and Atp7bΔIEC mice. Intestine-specific Atp7b deficit affects systemic metabolic pathways and intestine morphology, and hepatic metabolic perturbations are associated with intestinal dysfunction, independently from hepatic copper accumulation, providing evidence that WD phenotype is at least partially influenced by organ-specific ATP7B variants.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 0002-9440
e-ISSN 1525-2191
Zeitschrift American Journal of Pathology, The
Verlag Elsevier
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOX)