Restoration of copper metabolism and rescue of hepatic abnormalities in LEC rats, an animal model of Wilson disease, by expression of human ATP7B gene

Yan Meng, Ichiro Miyoshi, Masumi Hirabayashi, Mu Su, Yasumasa Mototani, Tadashi Okamura, Kunihiko Terada, Masatsugu Ueda, Katsuhiko Enomoto, Toshihiro Sugiyama, Noriyuki Kasai

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29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)208-219
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1690
Issue number3
DOIs
Publication statusPublished - 2004 Nov 5

Keywords

  • ATP7B
  • Copper metabolism
  • Fulminant hepatitis
  • LEC rat
  • Transgenic rat
  • Wilson disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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