Hepatocyte GP73 expression in Wilson disease☆

Background/Aims

Wilson disease (WD) is a disorder of copper transport caused by mutations within the ATP7B gene. WD is phenotypically variable and can present with predominantly hepatic or neurologic manifestations. The mechanisms responsible for this variability are unknown. GP73, a Golgi membrane protein, is expressed in hepatocytes in response to acute and chronic liver disease.

Methods

Hepatocyte GP73 expression was examined in the livers of WD patients by semiquantitative immunohistochemistry. GP73 mRNA levels were measured in mice with a deletion of the WD gene (Atp7b^−/−) by real-time PCR, and these values were compared to the concomitant histological abnormalities and previously reported copper levels.

Results

Hepatocyte GP73 expression was more frequently observed in patients with hepatic versus neurologic presentation (79% vs. 30%, p<0.05). Furthermore, GP73 expression was significantly higher (44.7±14.0 vs. 2.0±0.81, p<0.05) in patients with hepatic phenotype. In Atp7b^−/− mice, GP73 mRNA was significantly elevated at 20–46 weeks of age, coincident with extensive hepatic inflammation and fibrosis, but not at 6 weeks, when hepatic histology was normal despite significant copper overload. GP73 mRNA levels normalized concomitantly with the resolution of hepatic injury at 60-weeks. However, in tumor-like nodules GP73 was strikingly elevated.

Conclusion

Increased hepatocyte GP73 expression is more commonly a feature of hepatic than neurologic WD, and is triggered in response to inflammation, fibrosis, and dysplasia, rather than copper overload.

Abbreviations: WD, Wilson disease, ATP7B, ATPase copper transporting, beta polypeptide, GP73, Golgi protein 73kDa, HCC, hepatocellular carcinoma, CNS, central nervous system, KFR, Kayser–Fleischer rings, Cpl, ceruloplasmin, H & E, hematoxylin & eosin, IH, immunohistochemistry, RT-PCR, real-time polymerase chain reaction, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, Dx, diagnosis, ATOX1, metallochaperone antioxidant-1, COMMD1, copper metabolism MURR1 domain, PLZF, promyelocytic leukemia zinc finger protein, MINT, Molecular INTeraction database

Keywords: Atp7b, Copper, Golgi, Knockout mouse, Liver