Mitochondrial iron accumulation exacerbates hepatic toxicity caused by hepatitis C virus core protein.

Patients with long-lasting hepatitis C virus (HCV) infection are at major risk of hepatocellular carcinoma (HCC). Iron accumulation in the livers of these patients is thought to exacerbate conditions of oxidative stress. Transgenic mice that express the HCV core protein develop HCC after the steatosis stage and produce an excess of hepatic reactive oxygen species (ROS).

High ubiquitous mitochondrial creatine kinase expression in hepatocellular carcinoma denotes a poor prognosis with highly malignant potential.

We previously reported the increased serum mitochondrial creatine kinase (MtCK) activity in patients with hepatocellular carcinoma (HCC), mostly due to the increase in ubiquitous MtCK (uMtCK), and high uMtCK mRNA expression in HCC cell lines. We explored the mechanism(s) and the relevance of high uMtCK expression in HCC. In hepatitis C virus core gene transgenic mice, known to lose mitochondrial integrity in liver and subsequently develop HCC, uMtCK mRNA and protein levels were increased in HCC tissues but not in non-tumorous liver tissues.

Pathogenesis of lipid metabolism disorder in hepatitis C: polyunsaturated fatty acids counteract lipid alterations induced by the core protein.

Background & Aims: Disturbance in lipid metabolism is one of the features of chronic hepatitis C, being a crucial determinant of the progression of liver fibrosis. Experimental studies have revealed that the core protein of hepatitis C virus (HCV) induces steatosis.

Methods: The activities of fatty acid metabolizing enzymes were determined by analyzing the fatty acid compositions in HepG2 cells with or without core protein expression.

Hepatitis C virus core protein compromises iron-induced activation of antioxidants in mice and HepG2 cells.

One of the characteristics of hepatitis C virus (HCV) infection is the unusual augmentation of oxidative stress, which is exacerbated by iron accumulation in the liver, as observed frequently in hepatitis C patients. Using a transgenic mouse model, the core protein of HCV was shown previously to induce the overproduction of reactive oxygen species (ROS) in the liver. In the present study, the impact of iron overloading on the oxidant/antioxidant system was examined using this mouse model and cultured cells.

Tacrolimus ameliorates metabolic disturbance and oxidative stress caused by hepatitis C virus core protein: analysis using mouse model and cultured cells.

Hepatic steatosis and insulin resistance are factors that aggravate the progression of liver disease caused by hepatitis C virus (HCV) infection. In the pathogenesis of liver disease and metabolic disorders in HCV infection, oxidative stress due to mitochondrial respiratory chain dysfunction plays a pivotal role. Tacrolimus (FK506) is supposed to protect mitochondrial respiratory function.

Molecular basis for the synergy between alcohol and hepatitis C virus in hepatocarcinogenesis.

Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). In addition, heavy alcohol use has been linked with earlier progression to HCC in chronic hepatitis C patients. However, in the pathogenesis of HCV-associated HCC, it still remains controversial as to whether the virus plays a direct or an indirect role, and as to how alcohol operates in the acceleration of HCC development.

Hepatitis C virus core protein exerts an inhibitory effect on suppressor of cytokine signaling (SOCS)-1 gene expression.

Background/aims: Suppressor of cytokine signaling (SOCS)-1, a negative feedback regulator of cytokine signaling pathway, also has a tumor suppressor activity, the silencing of its gene by hypermethylation is suggested to contribute to hepatocarcinogenesis. We studied the effect of the core protein of hepatitis C virus (HCV) on the expression of SOCS-1 gene.

Methods: HCV core gene transgenic mice, which develop hepatocellular carcinoma late in life, HepG2 cells expressing the core protein, and human liver tissues were analyzed.