Hepatocyte GP73 expression in Wilson disease.
OBJECTIVE
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.


CONCLUSIONS
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.
Wright
Lorinda M
LM
Division of Gastroenterology, Hepatology and Nutrition, Loyola University Medical Center, Maywood, IL 60153, USA. LMWright@lumc.edu
Huster
Dominik
D
Lutsenko
Svetlana
S
Wrba
Fritz
F
Ferenci
Peter
P
Fimmel
Claus J
CJ
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D005260:Female; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006527:Hepatolenticular Degeneration / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D055815:Young Adult
D015415:Biomarkers; D027682:Cation Transport Proteins; C410824:GOLM1 protein, human; C546580:Golm1 protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases