Characterization of liver histopathology in a transgenic mouse model expressing genotype 1a hepatitis C virus core and envelope proteins 1 and 2

Abstract

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma worldwide. The purpose of this study was to determine how the HCV structural proteins affect the dynamic structural and functional properties of hepatocytes and measure the extra-hepatic manifestations induced by these viral proteins. A transgenic mouse model was established by expressing core, E1 and E2 proteins downstream of a CMV promoter. HCV RNA was detected using RT-PCR in transgenic mouse model tissues, such as liver, kidney, spleen and heart. Expression of the transgene was analysed by real-time PCR to quantify viral RNA in different tissues at different ages. Immunofluorescence analysis revealed the expression of core, E1 and E2 proteins predominantly in hepatocytes. Lower levels of protein expression were detected in spleen and kidneys. HCV RNA and viral protein expression increased in the liver with age. Histological analysis of liver cells demonstrated steatosis in transgenic mice older than 3 months, which was more progressed with age. Electron microscopy analysis revealed alterations in nuclei, mitochondria and endoplasmic reticulum. HCV structural proteins induce a severe hepatopathy in the transgenic mouse model. These mice became more prone to liver and lymphoid tumour development and hepatocellular carcinoma. In this model, the extra-hepatic effects of HCV, which included swelling of renal tubular cells, were mild. It is likely that the HCV structural proteins mediate some of the histological alterations in hepatocytes by interfering with lipid transport and liver metabolism.

Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

“…HCV-associated HCC has been reported to promote tumor growth and metastasis due to an increased recurrence after liver resection (8). In addition, expression of HCV structural proteins in transgenic mouse liver may contribute to the development of hepatic steatosis, fibrosis, and HCC (41,42). However, the underlying mechanisms responsible for the metastatic spread of HCV-induced HCC are not fully elucidated.…”

Helicobacter pyloriinfection does not promote hepatocellular cancer in a transgenic mouse model of hepatitis C virus pathogenesis

“…24,25 This difference may be due in part to the mixed genetic background in our model since another HCV transgenic mouse model on B6C3F1 and B6C3F2 genetic backgrounds was characterized by more females than males developing hepatic steatosis. 43 In addition, subsequent generations of FL-N/35 mice no longer developed spontaneous liver tumors. 27 The tumor promoting effects of the HCV transgene depend on the host genetic background.…”

Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein

“…The core protein binds to cellular proteins, suppresses or enhances apoptosis, and modulates the transcription of some host genes. 1 In addition, transgenic mice expressing the core protein develop HCC, [2][3][4] indicating a direct contribution of the core protein to the pathogenesis of hepatitis C.…”

“…2,5,6 In addition, the double structure of mitochondrial membranes is disrupted in hepatocytes of core-gene transgenic mice. [2][3][4] Evidence suggests that the core protein modulates some mitochondrial functions, including fatty acid ␤-oxidation, the impairment of which may induce lipid abnormalities and hepatic steatosis. In addition, the mitochondrion is an important source of reactive oxygen species (ROS).…”