Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein.
OBJECTIVE
Despite the evidence of hepatic iron overload in patients with chronic hepatitis C, it remains unknown if iron overload is related to hepatocarcinogenesis in this condition. The aim of this study was to determine whether iron overload contributes to development of hepatocellular carcinoma (HCC) in transgenic mice expressing the hepatitis C virus (HCV) polyprotein.


METHODS
Male C57BL/6 transgenic mice expressing the HCV polyprotein and nontransgenic littermates were fed an excess-iron diet or control diet. Mice in each group were assessed for altered liver morphology and function and the development of liver tumors.


RESULTS
Hepatic iron concentrations in mice fed the excess-iron diet were comparable to those of patients with chronic hepatitis C. There was no inflammation in transgenic and nontransgenic livers. Compared with mice in 3 other groups, transgenic mice fed the excess-iron diet showed marked hepatic steatosis including the centrilobular microvesicular type, ultrastructural alterations of the mitochondria and decreased degradation activity of fatty acid at 6 months, and greater hepatic content of lipid peroxidation products and 8-hydroxy-2'-deoxyguanosine at 12 months after initiation of feeding. The number of proliferating hepatocytes was significantly increased in mice fed the excess-iron diet but was not different between transgenic and nontransgenic mice. Hepatic tumors including HCC developed in 5 of 11 (45%) transgenic mice fed the excess-iron diet but not in mice in other groups at 12 months after initiation of feeding.


CONCLUSIONS
Iron overload induces mitochondrial injury and increases the risk of HCC development in transgenic mice expressing the HCV polyprotein.
Furutani
Takakazu
T
Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine, Ube, Japan.
Hino
Keisuke
K
Okuda
Michiari
M
Gondo
Toshikazu
T
Nishina
Sohji
S
Kitase
Akira
A
Korenaga
Masaaki
M
Xiao
Shu-Yuan
SY
Weinman
Steven A
SA
Lemon
Stanley M
SM
Sakaida
Isao
I
Okita
Kiwamu
K
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000150:complications*; D008111:Liver Function Tests; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020815:Polyproteins / Q000235:genetics / Q000378:metabolism*; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D014758:Viral Core Proteins / Q000032:analysis*
D016207:Cytokines; D018836:Inflammation Mediators; D020815:Polyproteins; D012333:RNA, Messenger; D014758:Viral Core Proteins; D007501:Iron