Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid

Wooton-Kee, CR; Jain, AK; Wagner, M; Grusak, MA; Finegold, MJ; Lutsenko, S; Moore, DD.
Elevated copper impairs hepatic nuclear receptor function in Wilson's disease.
J Clin Invest. 2015; 125(9):3449-3460 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG


Autor/innen der Med Uni Graz:
Wagner Martin

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Number of Figures: 6
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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.
Find related publications in this database (using NLM MeSH Indexing)
ATP Binding Cassette Transporter, Sub-Family B - deficiency
ATP Binding Cassette Transporter, Sub-Family B - genetics
ATP Binding Cassette Transporter, Sub-Family B - metabolism
Adenosine Triphosphatases - genetics
Adenosine Triphosphatases - metabolism
Adult -
Animals -
Cation Transport Proteins - genetics
Cation Transport Proteins - metabolism
Cholestasis, Intrahepatic - genetics
Cholestasis, Intrahepatic - metabolism
Cholestasis, Intrahepatic - pathology
Copper - metabolism
Copper-transporting ATPases -
Female -
Hepatolenticular Degeneration -
Humans -
Liver - metabolism
Liver - pathology
Male -
Mice -
Mice, Knockout -
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - metabolism
Response Elements -

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