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Title: Elevated copper impairs hepatic nuclear receptor function in Wilson's disease

Author
item WOOTEN-KEE, CLAVIA - Baylor College Of Medicine
item JAIN, AJAY - St Louis University
item WAGNER, MARTIN - Medical University Of Graz
item Grusak, Michael
item FINEGOLD, MILTON - Baylor College Of Medicine
item LUTSENKO, SVETLANA - Johns Hopkins University
item MOORE, DAVID - Baylor College Of Medicine

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/17/2015
Publication Date: 9/1/2015
Publication URL: http://handle.nal.usda.gov/10113/62760
Citation: Wooten-Kee, C.R., Jain, A.K., Wagner, M., Grusak, M.A., Finegold, M.J., Lutsenko, S., Moore, D.D. 2015. Elevated copper impairs hepatic nuclear receptor function in Wilson's disease. Journal of Clinical Investigation. 125(9):3449-3460.

Interpretive Summary: Copper is an important dietary nutrient that serves many functions in the human body. We are interested in understanding how the liver processes copper for its own use, as well as for use throughout the rest of the body. Copper coming from various food sources is absorbed in the gut and some of this copper is delivered to the liver via the blood supply. The liver then moves copper into different cellular compartments for delivery back into blood circulation, or into bile. Bile is a compound that is released from the liver into the gut, to aid in the digestion of fats. We have studied mice with an altered ability to transport copper within the liver, which results in an over-accumulation of copper in their livers. In humans, this same condition is seen in people with a condition called Wilson's disease. We have studied the mice to understand what the improper elevated concentration of copper does to the liver. We have learned that the copper interferes with the production of proteins that regulate fat synthesis in the liver. This leads to fatty livers, which can impair liver function. These results are important, because they will allow us to manipulate diets to help alleviate copper-related ailments in humans, while ensuring adequate intakes of dietary copper.

Technical 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, HNF4-alpha, 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.