Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) is a major cause of chronic liver disease that frequently leads to steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCV core protein is not only a component of viral particles but also a multifunctional protein because liver steatosis and HCC are developed in HCV core gene-transgenic (CoreTg) mice. Proteasome activator PA28gamma/REGgamma regulates host and viral proteins such as nuclear hormone receptors and HCV core protein. Here we show that a knockout of the PA28gamma gene induces the accumulation of HCV core protein in the nucleus of hepatocytes of CoreTg mice and disrupts development of both hepatic steatosis and HCC. Furthermore, the genes related to fatty acid biosynthesis and srebp-1c promoter activity were up-regulated by HCV core protein in the cell line and the mouse liver in a PA28gamma-dependent manner. Heterodimer composed of liver X receptor alpha (LXRalpha) and retinoid X receptor alpha (RXRalpha) is known to up-regulate srebp-1c promoter activity. Our data also show that HCV core protein enhances the binding of LXRalpha/RXRalpha to LXR-response element in the presence but not the absence of PA28gamma. These findings suggest that PA28gamma plays a crucial role in the development of liver pathology induced by HCV infection.
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PMID:Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. 1723 12

Worldwide approximately 200 million people are chronically infected with hepatitis C virus (HCV). Chronic HCV infection represents the leading cause of liver cirrhosis and the main indication for liver transplantation in the western world. In addition, chronic HCV infection is associated with numerous clinical manifestations, including type 2 diabetes. An obvious and frequently suggested explanation for the connection between HCV infection and type 2 diabetes is that cirrhosis by itself causes insulin resistance. However, the prevalence of type 2 diabetes in HCV cirrhosis is higher than in HBV cirrhosis (23.6% vs 9.4%). This suggests that HCV infection by itself can lead to insulin resistance and predispose to the onset of type 2 diabetes. First, HCV core protein induces hepatic steatosis by inhibition of microsomal triglyceride transfer protein and hepatic steatosis causes insulin resistance. Secondly, HCV core protein inhibits, through elevation of TNF-alfa and other factors, the insulin-signalling pathways causing insulin resistance. Moreover, recent data strongly suggest that insulin resistance is an important predictor of poor response to antiviral therapy in chronic hepatitis patients treated with peginterferon plus ribavirin.
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PMID:Hepatitis C and insulin resistance: mutual interactions. A review. 1754 92

Liver cirrhosis is reportedly one of the conditions preceding peripheral-type intrahepatic cholangiocarcinoma but not hilar/perihilar cholangiocarcinoma. Herein, we report a case of perihilar cholangiocarcinoma arising in a hepatitis C virus-related cirrhotic liver. The patient was a 69-year-old man. He was diagnosed with hepatitis C virus-related chronic hepatitis at the age of 56 years, and 9 years later, multiple hepatocellular carcinomas were detected by imaging modalities. Despite treatments, including chemotherapy, he died of hepatic failure at the age of 69 years. At autopsy, in addition to multiple nodules of hepatocellular carcinoma, we found a white mucinous and fibrous tumor spreading from the hepatic hilum to the periphery along the left lateral segmental bile ducts in the advanced cirrhotic liver. This tumor was histologically a cholangiocarcinoma that involved mainly the peribiliary glands and showed variable cystic dilation, suggesting that it might have been derived from these peribiliary glands. Immunohistochemically, the cholangiocarcinoma cells were positive for cytokeratin 7 and mucin core protein 1, and negative for cytokeratin 20 and mucin core protein 2. Hilar/perihilar cholangiocarcinoma arising in hepatitis C virus-related liver cirrhosis has rarely been reported. This case warrants further studies to clarify the possible involvement of hepatitis C virus in tumorigenesis of hilar/perihilar cholangiocarcinoma.
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PMID:Perihilar cholangiocarcinoma arising in hepatitis C virus-related liver cirrhosis with hepatocellular carcinoma. 1770 Nov 35

Hepatitis C virus (HCV) infection is the main cause for chronic hepatitis, leading to cirrhosis and hepatic carcinoma. Virally induced immune dysfunction has been called as the cause for viral persistence. Previous results demonstrate that CD4 Jurkat cells stably expressing the HCV core protein show an increased activation of NFAT transcription factor and an impaired IL-2 promoter activity, affecting intracellular signaling pathways in a manner that mimics clonal anergy. We had shown previously that NFAT activates a transcriptional program, ensuing in immunological tolerance. In the present work, we have engineered lentiviral vectors expressing the HCV core to analyze the events, which unfold in the initial phase of HCV core-induced anergy. We show that genes initially described to be up-regulated by ionomycin-induced anergy in mice are also up-regulated in humans, not only by ionomycin but also by HCV core expression. We also show that HCV core is sufficient to cause NFAT nuclear translocation and a slow-down in cell-cycle progression, and using whole genome microarrays, we identify novel genes up-regulated in Jurkat cells expressing HCV core. The relevance of our results is highlighted by the presence of HCV in CD4 T cells from HCV chronically infected patients.
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PMID:Hepatitis C virus core protein up-regulates anergy-related genes and a new set of genes, which affects T cell homeostasis. 1771 76

Chronic hepatitis B is probably the major cause of cirrhosis and hepatocellular carcinoma. The detection of the hepatitis B virus surface antigen (HBsAg) and HBV core protein, the e antigen (HBeAg), indicates infection with the hepatitis B virus and replication activity, respectively. Fructus schisandrae containing compound (KY88) may affect the elimination of HBV, strengthen the immune system, as well as stimulate liver cell regeneration. The present study was conducted to demonstrate the ability of KY88 in inhibiting hepatocellular carcinoma cell proliferation and secretions of HBsAg and HBeAg. The hepatocellular carcinoma cell line HB-8064 was treated by KY88 followed by the measurement of cell proliferation rate and secretions of HBsAg and HBeAg on days 1, 3, 5, and 7. A semi-quantitative RT-PCR method was used to quantify the expression of the mRNA. Seventy Sprague-Dawley rats were fed for 28days with purified KY88 for a toxicity test. The expression of surface and e antigens was lower when the cells were treated for a longer time with KY88 or when the doses were higher. One-way ANOVA analysis confirmed the mRNA content of HBsAg to be significantly less than control. The body weight did not show a significant difference compared to the control group. Fructus schisandrae-containing compound (KY88) was potentially effective in suppressing the proliferation of hepatocellular carcinoma cells. The decreased secretion and gene expression of HBsAg and HBeAg might restrict the growth of tumour masses.
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PMID:Fructus schisandrae (Wuweizi)-containing compound inhibits secretion of HBsAg and HBeAg in hepatocellular carcinoma cell line. 1790 89

Complex hepatitis B virus (HBV) variants with mutations in core promoter (Cp) plus deletions in the C gene and/or preS region--that are associated with development of liver cirrhosis in renal transplant recipients--show a drastically changed phenotype with altered transcription and disturbed surface and core protein expression. Here, we analyzed the replication phenotype of six different defective variant genomes, isolated from two patients, after co-transfection with HBV wild-type (wt) in varying proportions. Both in HuH7 and HepG2 cells, the variants showed enhanced replication and enrichment in the different transfected variant-wt mixtures. Contrary to artificial variants with only C gene deletions in wt context, the original complex variants as well as wt genomes carrying C gene and Cp mutations of the variants did mostly not suppress wt replication. Thus, the Cp mutations compensate the suppression of wt by C gene deletions and furthermore enhance the replication level.
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PMID:Co-replication analyses of naturally occurring defective hepatitis B virus variants with wild-type. 1806 Dec 29

Hepatitis C virus (HCV) is a major cause of chronic liver diseases, including steatosis, cirrhosis and hepatocellular carcinoma, and epidemiological studies indicate that HCV is also associated with insulin resistance and type 2 diabetes mellitus. The HCV core protein is not only a viral structural component but also a pathogenic factor, since its expression leads to the development of liver steatosis, insulin resistance and hepatocellular carcinoma in mice. The nuclear proteasome activator PA28gamma/REGgamma, which specifically binds to the core protein, is required for the virulence of the core protein. Elucidation of the mechanisms by which HCV core protein participates in the above conditions may provide clues toward the development of novel therapeutic measures for chronic hepatitis C.
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PMID:Hepatitis C virus core protein: its coordinate roles with PA28gamma in metabolic abnormality and carcinogenicity in the liver. 1832 62

Hepatitis C virus (HCV) infects approximately 170 million people worldwide including 2 million in Japan and induces serious chronic hepatitis that results in the development of steatosis, cirrhosis and ultimately hepatocellular carcinoma. The current combination therapy using pegylated interferon alpha and a nucleotide analogue ribavirin achieved a sustained virological response in about half population of individuals infected with HCV genotypes la and lb. More than two-thirds of the HCV-positive population has been chronically infected with genotype 1 in Western countries and Japan. Therefore, more effective therapeutics and preventative measures are needed for the treatment of hepatitis C patients who are not responsive to the current chemotherapy. HCV core protein is well known to be the viral capsid protein as well as the pathogenic factor that induces steatosis and hepatocellular carcinoma in the transgenic mice. In this review, we summarize the current status of our knowledge regarding the molecular mechanism by which HCV core protein induces liver steatosis and hepatocellular carcinoma and discuss on a future perspective for the development of novel therapeutics for chronic hepatitis C.
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PMID:[Pathogenesis of hepatitis C virus]. 1835 52

Persistent infection with the hepatitis C virus (HCV) is a major risk factor for the development of liver cirrhosis and hepatocellular carcinoma. With an estimated about 3% of the world population infected with this virus, the lack of a prophylactic vaccine and a selective therapy, chronic hepatitis C currently is a main indication for liver transplantation. The establishment of cell-based replication and virus production systems has led to first insights into the functions of HCV proteins. However, the role of nonstructural protein 5A (NS5A) in the viral replication cycle is so far not known. NS5A is a membrane-associated RNA-binding protein assumed to be involved in HCV RNA replication. Its numerous interactions with the host cell suggest that NS5A is also an important determinant for pathogenesis and persistence. In this study we show that NS5A is a key factor for the assembly of infectious HCV particles. We specifically identify the C-terminal domain III as the primary determinant in NS5A for particle formation. We show that both core and NS5A colocalize on the surface of lipid droplets, a proposed site for HCV particle assembly. Deletions in domain III of NS5A disrupting this colocalization abrogate infectious particle formation and lead to an enhanced accumulation of core protein on the surface of lipid droplets. Finally, we show that mutations in NS5A causing an assembly defect can be rescued by trans-complementation. These data provide novel insights into the production of infectious HCV and identify NS5A as a major determinant for HCV assembly. Since domain III of NS5A is one of the most variable regions in the HCV genome, the results suggest that viral isolates may differ in their level of virion production and thus in their level of fitness and pathogenesis.
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PMID:Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. 1836 81

Human hepatitis B virus (HBV) causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. Here we report that HBV core protein interacts with a cellular SKIP (skeletal muscle and kidney enriched inositol phosphatase) protein, an endoplasmic reticulum-located phosphoinositide 5-phosphatase, both in vivo and in vitro. The minimal sequence required for interaction is the amino acid region from 116 to 149 for the core protein and the SKIP carboxyl homology (SKICH) domain for SKIP. When HBV replicates in HuH-7 cells, overexpressed SKIP localizes to nucleus in addition to ER and suppresses HBV gene expression and replication. SKIP loses its nuclear localization and suppressive effect during replication of a core-negative HBV mutant. HBV gene expression is enhanced significantly when endogenous SKIP expression is knocked down by a SKIP-specific siRNA. SKIP mutation analysis shows that its 5-phosphatase activity is not required for the suppressive effect and that the suppression domain maps to amino acids 199-226. These results demonstrate that SKIP is translocated from endoplasmic reticulum into nucleus through its interaction with core protein and suppresses HBV gene expression via a novel suppression domain.
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PMID:Suppression of hepatitis B viral gene expression by phosphoinositide 5-phosphatase SKIP. 1877 50


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