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Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B −/− (Wilson disease) mice
Author(s) -
Hamilton James P.,
Koganti Lahari,
Muchenditsi Abigael,
Pendyala Venkata S.,
Huso David,
Hankin Joseph,
Murphy Robert C.,
Huster Dominik,
Merle Uta,
Mangels Christopher,
Yang Nan,
Potter James J.,
Mezey Esteban,
Lutsenko Svetlana
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28406
Subject(s) - liver x receptor , retinoid x receptor , pathogenesis , endocrinology , medicine , fatty liver , hepatology , liver x receptor alpha , liver disease , receptor , retinoid x receptor alpha , agonist , wilson's disease , biology , nuclear receptor , disease , biochemistry , gene , transcription factor
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. (H epatology 2016;63:1828‐1841)