Hepatitis B Virus Alters the Antioxidant System in Transgenic Mice and Sensitizes Hepatocytes to Fas Signaling

PLOS ONE, Dec 2019

Hepatitis B virus (HBV) is a major etiological factor of hepatocellular carcinoma (HCC). However, the precise pathogenetic mechanisms linking HBV infection and HCC remain uncertain. It has been reported that decreased antioxidant enzyme activities are associated with severe liver injury and hepatocarcinogenesis in mouse models. It is unclear if HBV can interfere with the activities of antioxidant enzymes. We established a HBV transgenic mouse line, which spontaneously developed HCC at 2 years of age. We studied the activities of the antioxidant enzymes in the liver of the HBV transgenic mice. Our results showed that the antioxidant enzymes glutathione peroxidase and superoxide dismutase 2 were down-regulated in HBV transgenic mice and correlated with JNK activation. HBV enhanced the Fas-mediated activation of caspase 6, caspase 8 and JNK without enhancing the activation of caspase 3 and hepatocellular apoptosis. As a proper redox balance is important for maintaining cellular homeostasis, these effects of HBV on the host antioxidant system and Fas-signaling may play an important role in HBV-induced hepatocarcinogenesis.

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Hepatitis B Virus Alters the Antioxidant System in Transgenic Mice and Sensitizes Hepatocytes to Fas Signaling

Yen TSB (2012) Hepatitis B Virus Alters the Antioxidant System in Transgenic Mice and Sensitizes Hepatocytes to Fas Signaling. PLoS ONE 7(5): e36818. doi:10.1371/journal.pone.0036818 Hepatitis B Virus Alters the Antioxidant System in Transgenic Mice and Sensitizes Hepatocytes to Fas Signaling Qian Wang 0 Bing Na 0 Jing-hsiung James Ou 0 Lynn Pulliam 0 T. S. Benedict Yen 0 Jean-Pierre Vartanian, Institut Pasteur, France 0 1 Department of Pathology, University of California San Francisco , San Francisco , California, United States of America, 2 Pathology Service 113B, VA Medical Center , San Francisco , California, United States of America, 3 Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States of America, 4 Department of Laboratory Medicine, University of California San Francisco, VA Medical Center , San Francisco, California , United States of America Hepatitis B virus (HBV) is a major etiological factor of hepatocellular carcinoma (HCC). However, the precise pathogenetic mechanisms linking HBV infection and HCC remain uncertain. It has been reported that decreased antioxidant enzyme activities are associated with severe liver injury and hepatocarcinogenesis in mouse models. It is unclear if HBV can interfere with the activities of antioxidant enzymes. We established a HBV transgenic mouse line, which spontaneously developed HCC at 2 years of age. We studied the activities of the antioxidant enzymes in the liver of the HBV transgenic mice. Our results showed that the antioxidant enzymes glutathione peroxidase and superoxide dismutase 2 were down-regulated in HBV transgenic mice and correlated with JNK activation. HBV enhanced the Fas-mediated activation of caspase 6, caspase 8 and JNK without enhancing the activation of caspase 3 and hepatocellular apoptosis. As a proper redox balance is important for maintaining cellular homeostasis, these effects of HBV on the host antioxidant system and Fas-signaling may play an important role in HBV-induced hepatocarcinogenesis. - Funding: This work was supported by grants from the National Institutes of Health (RO1CA55578, P30DK26743 and PO1CA123328). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Intracellular reactive oxygen species (ROS) levels are tightly controlled by four primary antioxidant enzymes superoxide dismutase (SOD) 1 and 2 (CuZnSOD and MnSOD), glutathione peroxidase (GPx) and catalase. Superoxide radicals are converted into hydrogen peroxide by SOD 1 and 2, and hydrogen peroxide is converted into water by catalase and GPx [1,2]. Oxidative stress can result from increased production of ROS and/or diminished levels of antioxidants including the activities of antioxidant enzymes [3]. Hepatocellula carcinoma (HCC) is the third leading cause of cancer death [4]. There are several published reports to show that decreased antioxidant enzyme activities are associated with severe liver injury and hepatocarcinogenesis in mouse models. For example, SOD1 deficient (Sod12/2) mice have increased incidence to develop liver nodular hyperplasia or HCC [5]. GPx deficient (Gpx2/2) mice are more susceptible to liver injuryinduced by tumor necrosis factor a (TNFa), anti-Fas antibody and oxidant paraquat [6,7,8]. Moreover, when challenged with oxidant paraquat, C-Jun amino-terminal kinases (JNK) are more activated in GPx deficient mice than in wild type mice [7]. The correlation between aberrant activation of JNK and hepatocarcinogenesis is observed in liver-specific deletion of p38a and IKKb mouse models [9,10]. In a liver-specific deletion of IKKb mouse model, diethylnitrosamine (DEN)-induced ROS production may contribute to sustained JNK activation due to oxidation and inhibition of JNK-inactivating phosphatases [11]. JNK1 has also been reported to be activated in human HCC tissues compared to adjacent non-cancerous tissues, among which 70% are with hepatitis B virus (HBV) infection. However, the mechanism for JNK1 activation is unknown [12]. Both HBV and hepatitis C virus (HCV) are the major etiological factors of HCC [13,14]. Lipid peroxidation has been detected in both HBV and HCV chronically infected patients, especially those with cirrhosis [15,16]. Both in vitro and in vivo evidences demonstrate that HCV core protein can induce ROS production and corresponding elevated antioxidant response as shown by up-regulation of the mRNA of antioxidant genes, including GPx, increased catalase activity and decreased total and reduced glutathione level [17,18]. However, it is unclear if HBV can interfere with the activities of antioxidant enzymes. We established a HBV transgenic mouse line, which carries the 1.3 mer over-length HBV genome and productively replicates HBV in the liver. Due to immune tolerance, the HBV transgenic mice do no (...truncated)


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Qian Wang, Bing Na, Jing-hsiung James Ou, Lynn Pulliam, T. S. Benedict Yen. Hepatitis B Virus Alters the Antioxidant System in Transgenic Mice and Sensitizes Hepatocytes to Fas Signaling, PLOS ONE, 2012, Volume 7, Issue 5, DOI: 10.1371/journal.pone.0036818