title: Restoration of copper metabolism and rescue of hepatic abnormalities in LEC rats, an animal model of Wilson disease, by expression of human ATP7B gene.
abstract: Hepatic abnormalities in Long-Evans Cinnamon (LEC) rats, an animal model of Wilson disease (WD), were restored by the expression of the human ATP7B cDNA under the control of CAG promoter. Expression of ATP7B transcript and protein in the liver of the transgenic rats resulted in the restoration of biosynthesis of holoceruloplasmin and biliary copper excretion. Meanwhile, transgenic rats showed striking improvements in their hepatic abnormalities, i.e., rescue from fulminant hepatitis, late onset of hepatic cholangiofibrosis, suppression of hepatocellular carcinoma and much improved survival rates. Moreover, dramatic decreases were noted both in the levels of hepatic copper and iron in transgenic rats before the occurrence of hepatitis. These results indicated that the human ATP7B product compensated for the deficiency of the endogenous rattus protein and did function in intrahepatic copper transport by secreting copper into the plasma via incorporation into ceruloplasmin and by the excretion of copper into the bile, and that ATP7B is critical to hepatic dysfunctions in WD. This first successful transgenic rescue has important implications for the gene therapy of WD.
authors.affiliation: Institute for Animal Experimentation, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.forename: Ichiro
authors.initials: I
authors.lastname: Miyoshi
authors.forename: Masumi
authors.initials: M
authors.lastname: Hirabayashi
authors.forename: Mu
authors.initials: M
authors.lastname: Su
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Mototani
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Terada
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ueda
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Enomoto
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasai
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002570:Ceruloplasmin / Q000096:biosynthesis; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006520:Hepatitis, Animal / Q000235:genetics / Q000473:pathology; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000002:abnormalities* / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020332:Rats, Inbred LEC; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D019076:Transgenes / Q000235:genetics
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D007501:Iron; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases