Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus.
OBJECTIVE
The aim of this study was to determine whether expression of hepatitis C virus proteins alters hepatic morphology or function in the absence of inflammation.


METHODS
Transgenic C57BL/6 mice with liver-specific expression of RNA encoding the complete viral polyprotein (FL-N transgene) or viral structural proteins (S-N transgene) were compared with nontransgenic littermates for altered liver morphology and function.


RESULTS
FL-N transcripts were detectable only by reverse-transcription polymerase chain reaction, and S-N transcripts were identified in Northern blots. The abundance of viral proteins was sufficient for detection only in S-N transgenic animals. There was no inflammation in transgenic livers, but mice expressing either transgene developed age-related hepatic steatosis that was more severe in males. Apoptotic or proliferating hepatocytes were not significantly increased. Hepatocellular adenoma or carcinoma developed in older male animals expressing either transgene, but their incidence reached statistical significance only in FL-N animals. Neither was ever observed in age-matched nontransgenic mice.


CONCLUSIONS
Constitutive expression of viral proteins leads to common pathologic features of hepatitis C in the absence of specific anti-viral immune responses. Expression of the structural proteins enhances a low background of steatosis in C57BL/6 mice, while additional low level expression of nonstructural proteins increases the risk of cancer.
Lerat
Hervé
H
Department of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, Texas 77555-1019, USA.
Honda
Masao
M
Beard
Michael R
MR
Loesch
Kim
K
Sun
Jiaren
J
Yang
Yan
Y
Okuda
Michiari
M
Gosert
Rainer
R
Xiao
Shu-Yuan
SY
Weinman
Steven A
SA
Lemon
Stanley M
SM
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D005234:Fatty Liver / Q000473:pathology / Q000821:virology*; D005260:Female; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000473:pathology / Q000821:virology*; D008103:Liver Cirrhosis / Q000473:pathology / Q000821:virology; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D019076:Transgenes / Q000502:physiology; D014758:Viral Core Proteins / Q000235:genetics; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D015678:Viral Structural Proteins
D012333:RNA, Messenger; D014758:Viral Core Proteins; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; D015678:Viral Structural Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C107842:protein E1, Classical swine fever virus; C091015:glycoprotein E2, Hepatitis C virus