TY - JOUR
T1 - Hepatocyte GP73 expression in Wilson disease
AU - Wright, Lorinda M.
AU - Huster, Dominik
AU - Lutsenko, Svetlana
AU - Wrba, Fritz
AU - Ferenci, Peter
AU - Fimmel, Claus J.
N1 - Funding Information:
This study was supported by an NIH grant (R21 DK075659) to S.L. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Funding Information:
This study was supported by a VA Merit Award to C.J.F., a German Research Foundation Grant HU932/3-2 to D.H., and an NIH Grant (R21 DK075659) to S.L.
PY - 2009/9
Y1 - 2009/9
N2 - 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.
AB - 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.
KW - Atp7b
KW - Copper
KW - Golgi
KW - Knockout mouse
KW - Liver
UR - http://www.scopus.com/inward/record.url?scp=68049123103&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68049123103&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2009.05.029
DO - 10.1016/j.jhep.2009.05.029
M3 - Article
C2 - 19596473
AN - SCOPUS:68049123103
VL - 51
SP - 557
EP - 564
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 3
ER -