Non‐structural 5A protein of hepatitis C virus induces a range of liver pathology in transgenic mice

Wang, Aiguo; Lee, Dong Seok; Moon, Hyung–Bae; Kim, Jin Man; Cho, Kyung‐Hyun; Choi, Soo–Ho; Ha, Hojin; Han, Ying‐Hao; Kim, Dae‐Ghon; Hwang, Soon B.; Yu, Dae‐Yeul

doi:10.1002/path.2592

Cited by 55 publications

(56 citation statements)

References 41 publications

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“…7 to 9). In line with our observations, the NS5A-mediated induction of ROS production (68) and JNK activation (49) was reported previously by other investigators.…”

Section: Discussionsupporting

confidence: 81%

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Hepatitis C Virus Infection Promotes Hepatic Gluconeogenesis through an NS5A-Mediated, FoxO1-Dependent Pathway

Deng

Shoji

Ogawa

et al. 2011

J Virol

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Chronic hepatitis C virus (HCV) infection is often associated with type 2 diabetes.However, the precise mechanism underlying this association is still unclear. Here, using Huh-7.5 cells either harboring HCV-1b RNA replicons or infected with HCV-2a, we showed that HCV transcriptionally upregulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. In this way, HCV enhanced the cellular production of glucose 6-phosphate (G6P) and glucose. PEPCK and G6Pase gene expressions are controlled by the transcription factor forkhead box O1 (FoxO1). We observed that although neither the mRNA levels nor the protein levels of FoxO1 expression were affected by HCV, the level of phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells compared to the control cells, resulting in an increased nuclear accumulation of FoxO1, which is essential for sustaining its transcriptional activity. It was unlikely that the decreased level of FoxO1 phosphorylation was mediated through Akt inactivation, as we observed an increased phosphorylation of Akt at Ser473 in HCVinfected cells compared to control cells. By using specific inhibitors of c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS), we demonstrated that HCV infection induced JNK activation via increased mitochondrial ROS production, resulting in decreased FoxO1 phosphorylation, FoxO1 nuclear accumulation, and, eventually, increased glucose production. We also found that HCV NS5A mediated increased ROS production and JNK activation, which is directly linked with the FoxO1-dependent increased gluconeogenesis. Taken together, these observations suggest that HCV promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway.

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“…7 to 9). In line with our observations, the NS5A-mediated induction of ROS production (68) and JNK activation (49) was reported previously by other investigators.…”

Section: Discussionsupporting

confidence: 81%

“…Recently reported data suggest that ROS production is induced in NS5A-expressing cells (17) or in hepatocytes of NS5A transgenic mice (68). We therefore sough to determine whether NS5A contributes to increased hepatic gluconeogenesis through the induction of ROS production.…”

Section: Vol 85 2011mentioning

confidence: 99%

Hepatitis C Virus Infection Promotes Hepatic Gluconeogenesis through an NS5A-Mediated, FoxO1-Dependent Pathway

Deng

Shoji

Ogawa

et al. 2011

J Virol

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“…We along with other groups previously reported that HCV NS5A protein is involved in mitochondrial reactive oxygen species (ROS) production (11,13,38). Mitochondrial ROS generation is known to induce the autophagy pathway (22) and lysosomal membrane permeabilization (8).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Infection Suppresses GLUT2 Gene Expression via Downregulation of Hepatocyte Nuclear Factor 1α

Matsui

Shoji

Kaneda

et al. 2012

J Virol

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Hepatitis C virus (HCV) is the main cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV is a single-stranded, positive-sense RNA virus that is classified into the Flaviviridae family, Hepacivirus genus (21). More than 170 million people worldwide are chronically infected with HCV. The 9.6-kb HCV genome encodes a polyprotein of approximately 3,010 amino acids (aa). The polyprotein is cleaved co-and posttranslationally into at least 10 proteins by viral proteases and cellular signalases: the structural proteins core, E1, E2, and p7 and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B (21).Persistent HCV infection causes not only intrahepatic diseases but also extrahepatic manifestations, such as type 2 diabetes. Clinical and experimental data suggest that HCV infection is an additional risk factor for the development of diabetes (26,29,30). HCV-related glucose metabolic changes and insulin resistance have significant clinical consequences, such as accelerated fibrogenesis, reduced virological response to alpha interferon (IFN-␣)-based therapy, and increased incidence of hepatocellular carcinoma (29). Therefore, the molecular mechanism of HCV-related diabetes needs to be clarified.We have sought to identify a novel mechanism of HCV-induced diabetes. We previously demonstrated that HCV suppresses hepatocytic glucose uptake through downregulation of cell surface expression of glucose transporter 2 (GLUT2) in a human hepatoma cell line (19). The uptake of glucose into cells is conducted by facilitative glucose carriers, i.e., glucose transporters (GLUTs). GLUTs are integral membrane proteins that contain 12 membrane-spanning helices. To date, a total of 14 isoforms have been identified in the GLUT family (24). GLUT2 is expressed in the liver, pancreatic ␤-cells, hypothalamic glial cells, retina, and enterocytes. Glucose is transported into hepatocytes by GLUT2 (34). We previously reported that GLUT2 expression was reduced in hepatocytes obtained from HCV-infected patients (19). We also demonstrated that GLUT2 mRNA levels were lower in HCV replicon cells and in HCV J6/JFH1-infected cells than in the control cells. GLUT2 promoter activity was suppressed in HCV-replicating cells. However, the molecular mechanism of HCV-induced suppression of GLUT2 gene expression remains to be elucidated.In the present study, we aimed to clarify molecular mechanisms of HCV-induced suppression of GLUT2 gene expression. We analyzed transcriptional regulation of the GLUT2 promoter in HCV replicon cells. We demonstrate that HCV infection downregulates hepatocyte nuclear factor 1␣ (HNF-1␣) expression at both transcriptional and posttranslational levels, resulting in suppression of GLUT2 promoter. We propose that HCV-induced downregulation of HNF-1␣ may play a crucial role in glucose metabolic disorders caused by HCV. MATERIALS AND METHODSCell culture. The human hepatoma cell line Huh-7.5 (4) was kindly provided by Charles M. Rice (The Rockefeller University, New York, NY).

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“…Histopathology of chronic hepatitis C underscores the contribution of the immune system in the defense against the virus, whereby it contributes to formation of lymphoid follicles in portal tracts as well as abundant lymphocytic infiltrates and a high degree of mesenchymal reaction in the sinusoids [11] . Although some reports on transgenic mice containing virus genomic segments, as the core suggests a cytopathic effect with fatty metamorphosis of hepatocytes [12] , data from animal experiments and clinical observation give solid evidence that the liver damage is induced by the immune defense of the organism against the virus with innate basic immune mechanisms and a subsequent rigorous adaptive immune response [13] .…”

Section: Hepatitis Bmentioning

confidence: 99%

Pathology of Immune-Mediated Liver Injury

Dienes

Drebber²

2010

Dig Dis

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The liver is a special lymphoid organ with its own defense mechanism and it is prone to chronic viral and autoimmune diseases. All constituent liver cells are involved in immune mechanisms against foreign toxins and infectious agents: hepatocytes, Kupffer cells, endothelial cells, hepatic stellate cells and liver resident lymphocytes such as natural killer, natural killer T and dendritic cells. The first line of defense is held up by the innate immune system where the adaptive immune response is more antigen-specific, but needs a longer time to build up. Even in drug injury of the liver, the innate immune system is involved. There is activation of natural killer and natural killer T cells, and liver cell damage is induced mainly by the Fas and FasL pathways. In viral hepatitis, the mechanism of liver injury is mainly immune-mediated since almost none of the hepatitis viruses have turned out to be cytopathic by themselves. Cytotoxic T lymphocytes with CD8 epitopes are the most important effector cell population. The immune defense may be downregulated by regulatory T cell lymphocytes, PD1/PDL-positive lymphocytes or suppressor dendritic cells. In Epstein-Barr virus infection, liver cell injury does not seem to be due to direct antigen-specific CTLs, but the injury is assumingly induced by a bystander reaction from activated lymphocytes in the sinusoids. Autoimmune hepatitis is a paradigm of immune-mediated liver injury and has a special, but not pathognomonic, histopathology. The main effector lymphocytes belong to the CD8 population, which are antigen-specific; however, the mechanisms seem to be suppressed by regulatory T cells.

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Non‐structural 5A protein of hepatitis C virus induces a range of liver pathology in transgenic mice

Cited by 55 publications

References 41 publications

Hepatitis C Virus Infection Promotes Hepatic Gluconeogenesis through an NS5A-Mediated, FoxO1-Dependent Pathway

Hepatitis C Virus Infection Promotes Hepatic Gluconeogenesis through an NS5A-Mediated, FoxO1-Dependent Pathway

Hepatitis C Virus Infection Suppresses GLUT2 Gene Expression via Downregulation of Hepatocyte Nuclear Factor 1α

Pathology of Immune-Mediated Liver Injury

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