title: Elevated copper impairs hepatic nuclear receptor function in Wilson's disease.
abstract: Wilson's disease (WD) is an autosomal recessive disorder that results in accumulation of copper in the liver as a consequence of mutations in the gene encoding the copper-transporting P-type ATPase (ATP7B). WD is a chronic liver disorder, and individuals with the disease present with a variety of complications, including steatosis, cholestasis, cirrhosis, and liver failure. Similar to patients with WD, Atp7b⁻/⁻ mice have markedly elevated levels of hepatic copper and liver pathology. Previous studies have demonstrated that replacement of zinc in the DNA-binding domain of the estrogen receptor (ER) with copper disrupts specific binding to DNA response elements. Here, we found decreased binding of the nuclear receptors FXR, RXR, HNF4α, and LRH-1 to promoter response elements and decreased mRNA expression of nuclear receptor target genes in Atp7b⁻/⁻ mice, as well as in adult and pediatric WD patients. Excessive hepatic copper has been described in progressive familial cholestasis (PFIC), and we found that similar to individuals with WD, patients with PFIC2 or PFIC3 who have clinically elevated hepatic copper levels exhibit impaired nuclear receptor activity. Together, these data demonstrate that copper-mediated nuclear receptor dysfunction disrupts liver function in WD and potentially in other disorders associated with increased hepatic copper levels.
authors.forename: Clavia Ruth
authors.initials: CR
authors.lastname: Wooton-Kee
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Jain
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grusak
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lutsenko
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D005260:Female; D006527:Hepatolenticular Degeneration; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases