Biliary excretion of copper in LEC rat after introduction of copper transporting P‐type ATPase, ATP7B

Abstract

Wilson's disease, an autosomal recessive disorder, is characterized by the excessive accumulation of hepatic copper that results from reduced biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. The ATP7B gene, responsible for the disease, encodes a copper transporting P‐type ATPase. We previously demonstrated the involvement of ATP7B in hepatic copper secretion into plasma after the introduction of ATP7B into the Long‐Evans Cinnamon (LEC) rat, a rodent model of Wilson's disease. In this study we found the increased copper contents of the hepatic lysosomal fractions and bile in the LEC rats after ATP7B introduction, indicating the participation of ATP7B in the biliary excretory pathway for copper.

Copper-Induced Translocation of the Wilson Disease Protein ATP7B Independent of Murr1/COMMD1 and Rab7

“…58,59 The fact that Rab-GFP proteins faithfully mimic their endogenous counterparts has been characterized extensively. 46,58,60,61 Because endosomes and lysosomes have been implicated in the pathway of copper excretion, 9,42,[62][63][64] we compared ATP7B to a subset of well-established rab marker proteins of the endolysosomal pathway. Rab7 localized to late endosomes 46,54 was of special interest because a co-localization with WDP/ATP7B had been claimed.…”

“…5,6 Many different mutations distributed along the whole ATP7B gene lead to Wilson disease. 7,8 The WDP is critical for biliary excretion of copper 9 but also supplies copper ions for the ferroxidase ceruloplasmin, 10 which is the main copper containing protein of serum. 11 Copper transport defects may also lead to systemic copper deficiency when ATP7A, a related intestinal P-type ATPase, is mutated.…”

Clusterin and COMMD1 Independently Regulate Degradation of the Mammalian Copper ATPases ATP7A and ATP7B

“…WD is an autosomal recessive copper toxicity disorder (9). The ATP7B protein is a key liver protein that regulates the copper status of the body, primarily by regulating biliary copper excretion (12). In WD, copper accumulates to toxic levels in the liver and in 50% of cases, in the brain.…”

Molecular mechanism of copper transport in Wilson disease.

“…In addition to its ATP-driven copper transport role at the TGN where copper is incorporated into ceruloplasmin (25,26), the Wilson disease protein is also thought to be involved in the excretion of copper into bile at the canalicular membrane (27). The copper-stimulated trafficking of the transporter between the TGN and the canalicular membrane may involve the N terminus and is not clearly understood (28).…”