Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B(-/-) (Wilson disease) mice.

Abstract

UNLABELLED:

Wilson disease (WD) is a hepatoneurological disorder caused by mutations in the copper-transporter, ATP7B. Copper accumulation in the liver is a hallmark of WD. Current therapy is based on copper chelation, which decreases the manifestations of liver disease, but often worsens neurological symptoms. We demonstrate that in Atp7b(-/-) mice, an animal model of WD, liver function can be significantly improved without copper chelation. Analysis of transcriptional and metabolic changes in samples from WD patients and Atp7b(-/-) mice identified dysregulation of nuclear receptors (NRs), especially the liver X receptor (LXR)/retinoid X receptor heterodimer, as an important event in WD pathogenesis. Treating Atp7b(-/-) mice with the LXR agonist, T0901317, ameliorated disease manifestations despite significant copper overload. Genetic markers of liver fibrosis and inflammatory cytokines were significantly decreased, lipid profiles normalized, and liver function and histology were improved.

CONCLUSIONS:

The results demonstrate the major role of an altered NR function in the pathogenesis of WD and suggest that modulation of NR activity should be explored as a supplementary approach to improving liver function in WD. (Hepatology 2016;63:1828-1841).

• Authors: James P Hamilton, Lahari Koganti, Abigael Muchenditsi, Venkata S Pendyala, David Huso, Joseph Hankin, Robert C Murphy, Dominik Huster, Uta Merle, Christopher Mangels, Nan Yang, James J Potter, Esteban Mezey, Svetlana Lutsenko
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 63 Issue 6 Pg. 1828-41 (06 2016) ISSN: 1527-3350 [Electronic] United States
• PMID: 26679751 (Publication Type: Journal Article)
• Copyright: © 2015 by the American Association for the Study of Liver Diseases.

Chemical References

• Atp7a protein, mouse
• Cation Transport Proteins
• Hydrocarbons, Fluorinated
• Liver X Receptors
• Retinoid X Receptors
• Sulfonamides
• T0901317
• Copper
• Adenosine Triphosphatases
• Copper-Transporting ATPases

Topics

• Adenosine Triphosphatases (genetics)
• Animals
• Cation Transport Proteins (genetics)
• Copper (metabolism)
• Copper-Transporting ATPases
• Drug Evaluation, Preclinical
• Gene Expression Regulation (drug effects)
• Hepatolenticular Degeneration (drug therapy, genetics)
• Humans
• Hydrocarbons, Fluorinated (pharmacology, therapeutic use)
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Liver Function Tests
• Liver X Receptors (agonists, metabolism)
• Mice, Knockout
• Retinoid X Receptors (metabolism)
• Sulfonamides (pharmacology, therapeutic use)