Intestinal expression of metal transporters in Wilson’s disease

Adam Przybyłkowski,Anna Cybulska,Grażyna Gromadzka,Tomasz Grygorowicz,Anna Członkowska,Adriana Wawer

doi:10.1007/s10534-013-9668-5

Adam Przybyłkowski, Anna Cybulska + Show 4 more

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https://doi.org/10.1007/s10534-013-9668-5

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Abstract

In Wilson’s disease (WND), biallelic ATP7B gene mutation is responsible for pathological copper accumulation in the liver, brain and other organs. It has been proposed that copper transporter 1 (CTR1) and the divalent metal transporter 1 (DMT1) translocate copper across the human intestinal epithelium, while Cu-ATPases: ATP7A and ATP7B serve as copper efflux pumps. In this study, we investigated the expression of CTR1, DMT1 and ATP7A in the intestines of both WND patients and healthy controls to examine whether any adaptive mechanisms to systemic copper overload function in the enterocytes. Duodenal biopsy samples were taken from 108 patients with Wilson’s disease and from 90 controls. CTR1, DMT1, ATP7A and ATP7B expression was assessed by polymerase chain reaction and Western blot. Duodenal CTR1 mRNA and protein expression was decreased in WND patients in comparison to control subjects, while ATP7A mRNA and protein production was increased. The variable expression of copper transporters may serve as a defense mechanism against systemic copper overload resulting from functional impairment of ATP7B.

Highlights

Wilson’s disease (Online Mendelian Inheritance in Man [OMIM] 277900, WND) is an inherited autosomal recessive metabolic disorder characterized by impaired copper metabolism
It has been proposed that copper transporter 1 (CTR1) and the divalent metal transporter 1 (DMT1) translocate copper across the human intestinal epithelium, while CuATPases: ATP7A and ATP7B serve as copper efflux pumps
We investigated the expression of CTR1, DMT1 and ATP7A in the intestines of both WND patients and healthy controls to examine whether any adaptive mechanisms to systemic copper overload function in the enterocytes

Summary

Introduction

Wilson’s disease (Online Mendelian Inheritance in Man [OMIM] 277900, WND) is an inherited autosomal recessive metabolic disorder characterized by impaired copper metabolism. The affected gene is ATP7B, which encodes an intracellular membrane-spanning P-type adenosine triphosphatase (ATPase), a copper transporting protein abundant in hepatocytes (Frydman et al 1985). The mechanism of copper efflux from the enterocyte has been better defined It includes two proteins: ATP7A and ATP7B, both belonging to the P-type ATPase family of proteins translocating copper across cellular membranes in an adenosine triphosphate (ATP)dependant manner (Gupta and Lutsenko 2009). The ATP7B protein has been proposed as a modifier of intestinal copper absorption via copper excretion through the apical surface of the enterocyte and/or via vesicular sequestration (trapping) of copper within the cell (Gupta and Lutsenko 2009)

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