title: Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B(-/-) (Wilson disease) mice.
abstract: 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.
  
  
  
  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.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: James P
authors.initials: JP
authors.lastname: Hamilton
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Lahari
authors.initials: L
authors.lastname: Koganti
authors.affiliation: Physiology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Abigael
authors.initials: A
authors.lastname: Muchenditsi
authors.affiliation: Physiology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Pendyala
authors.affiliation: Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: David
authors.initials: D
authors.lastname: Huso
authors.affiliation: University of Colorado, Denver, CO.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hankin
authors.affiliation: University of Colorado, Denver, CO.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Deakoness Hospital, Leipzig, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Huster
authors.affiliation: University of Heidelberg, Heidelberg, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Merle
authors.affiliation: Physiology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Christopher
authors.initials: C
authors.lastname: Mangels
authors.affiliation: Physiology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: James J
authors.initials: JJ
authors.lastname: Potter
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Esteban
authors.initials: E
authors.lastname: Mezey
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.|Physiology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lutsenko
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D006527:Hepatolenticular Degeneration / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008111:Liver Function Tests; D000071518:Liver X Receptors / Q000819:agonists* / Q000378:metabolism; D018345:Mice, Knockout; D047488:Retinoid X Receptors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000251:Adenosine Triphosphatases; D027682:Cation Transport Proteins; D003300:Copper; D000073840:Copper-Transporting ATPases; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D047488:Retinoid X Receptors; D013449:Sulfonamides; C486201:Atp7a protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides