Hepatocytes and Hepatic Stellate Cells Carry Different Levels of DNA Damage due to Their Sensitivity to Oxidative Stress in Chronic Hepatitis B

Abstract

Hepatocellular carcinoma (HCC) and liver cirrhosis (LC) occur in spite of current antiviral therapies in patients with chronic hepatitis (CHB). It is not yet known why HCC and LC are related to hepatocytes and hepatic stellate cells (HSCs), respectively, in the same inflammation circumstances. The expression of the phosphorylated form of histone H2AX (γ-H2AX), a biomarker of DNA damage, was detected in hepatocytes and interstitial cells within the liver tissues of 69 patients with CHB using immunohistochemical assay and immunofluorescence colocalisation technique. Hydrogen peroxide (H₂O₂) was applied to establish an oxidative DNA damage model. Hepatocytes in CHB patients carried much higher levels of DNA damage than interstitial cells. The DNA damage-carried interstitial cells were confirmed to be HSCs. They lost the damaged DNA during differentiation into myofibroblasts near the foci of inflammatory necrosis. Hepatocyte was much more sensitive to oxidative stress and DNA damage than HSCs, but both MIHA and LX-2 repaired DNA damage efficiently in vitro. Hepatocytes carried much higher levels of DNA damage than HSCs due to their remarkable difference in sensitivity to inflammation-induced oxidative DNA damage. The different sensitivity may render hepatocytes and HSCs to be respectively involved in HCC and LC in the same inflammation circumstances.