Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There was an epidemic of non-A non-B hepatitis in a small area of a town in the central part of Japan, which began with an outbreak of several patients in 1981 and then spread extensively with the result that about one third of the inhabitants showed abnormality in serum liver function tests at the health check performed in 1985. We determined histological diagnoses on that occasion for 167 individuals of the abnormal population and recently assayed antibodies against hepatitis C virus (HCV) for most of their sera left available. Histologically, chronic active hepatitis (CAH) was the major pattern, accounting for 59.3% (99 cases) of the total. Others were chronic persistent hepatitis (CPH) (13.2%), chronic lobular hepatitis (CLH) (16.2%), liver cirrhosis (LC) (6.6%) and fatty liver (4.8%). In the serological studies, the newly developed system to detect antibodies against the viral core protein p 22 was found to be much more sensitive than the conventional system to detect anti C 100-3 antibodies. By using these two methods in combination, we found that 82% were antibody-positive, indicating strong implication of HCV in this epidemic. This was further supported by direct detection of the viral genome in patients' sera by polymerase chain reaction following reverse transcription. We further found a strong correlation between the histological inflammatory activity and the antibody prevalence, since nearly all (97.6%) of the CAH cases were antibody-positive by at least either of the antibody assays, while only about 50% were positive in the less active cases such as CPH and CLH.
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PMID:Correlation between detection of anti-viral antibody and histopathological disease activity in an epidemic of hepatitis C. 138 9

Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide, which finally leads to development of hepatocellular carcinoma. Chronic hepatitis C is characterized by several histological features in the liver which discriminate it from other forms of hepatitis: bile duct damage, lymphoid follicles and steatosis (fatty change). Little is known, however, about the role of HCV or its viral proteins in the pathogenesis of hepatitis. Recently, the core protein of HCV has been suggested to have a transcriptional regulatory function, and thereby to be involved in inducing phenotypic changes in hepatocytes. To clarify whether or not the HCV core protein has an effect on pathological phenotypes in the liver, two independent transgenic mouse lines carrying the HCV core gene were established. These mice developed progressive hepatic steatosis, indicating that the HCV core protein plays a direct role in the development of hepatic steatosis, which characterizes hepatitis C. This transgenic mouse system would be a good animal model for the study of pathogenesis in human HCV infection.
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PMID:Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. 922 25

Hepatitis C virus (HCV) is the main cause of chronic hepatitis worldwide. Chronic hepatitis ultimately results in the development of hepatocellular carcinoma (HCC). However, the mechanism of hepatocarcinogenesis in chronic HCV infection is still unclear. The ability of the core protein of HCV to modulate gene transcription, cell proliferation and cell death may be involved in the pathogenesis of HCC. Here, we report the development of HCC in two independent lines of mice transgenic for the HCV core gene, which develop hepatic steatosis early in life as a histological feature characteristic of chronic hepatitis C. After the age of 16 months, mice of both lines developed hepatic tumors that first appeared as adenomas containing fat droplets in the cytoplasm. Then HCC, a more poorly-differentiated neoplasia, developed from within the adenomas, presenting in a 'nodule-in-nodule' manner without cytoplasmic fat droplets; this closely resembled the histopathological characteristics of the early stage of HCC in patients with chronic hepatitis C. These results indicate that the HCV core protein has a chief role in the development of HCC, and that these transgenic mice provide good animal models for determining the molecular events in hepatocarcinogenesis with HCV infection.
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PMID:The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. 973 2

Hepatic steatosis has been reported as one of the characteristics which discriminates hepatitis C from other forms of hepatitis, besides lymphoid follicles and bile duct damage. However, it is unclear whether or not the presence of hepatitis C virus (HCV) itself is associated with the development of steatosis. The possibility that the HCV itself is directly related to the development of steatosis was examined. The intrahepatic core protein levels, as a marker of the HCV load, were correlated with the presence of steatosis in 43 patients with chronic hepatitis C. Among 43 patients studied by Western blotting, the core protein was detected in the liver in 27 (62.8%). On the other hand, hepatic steatosis was observed in 21 (48.8%) of the 43 patients. Importantly, the core protein was detectable in 19 (90.4%) of the 21 patients with steatosis, while it was detected in only 8 (36.4%) of the 22 patients without steatosis (P = 0.008). However, serum HCV-RNA levels as determined by the Amplicor monitor were not significantly different between patients with and without steatosis. Multivariate analysis showed that the serum alanine aminotransferase level (P = 0. 013), body mass index (P = 0.038), and intrahepatic HCV core protein positivity (P = 0.038) were the independent parameters best predictive of steatosis. These results indicate a close relationship between intrahepatic HCV and the development of steatosis, and suggest a possible role of the HCV itself or core protein in the pathogenesis of steatosis in human chronic hepatitis C.
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PMID:Steatosis and intrahepatic hepatitis C virus in chronic hepatitis. 1045 47

The mechanism of hepatocarcinogenesis in hepatitis C virus (HCV) infection is still undefined. One possibility is the involvement of oxidative stress, which can produce genetic mutations as well as gross chromosomal alterations and contribute to cancer development. We recently showed that after a long period, the core protein of HCV induces hepatocellular carcinoma (HCC) in transgenic mice with marked hepatic steatosis but without inflammation, indicating a direct involvement of HCV in hepatocarcinogenesis. To elucidate the biochemical events before the development of HCC, we examined several parameters of oxidative stress and redox homeostasis in a mouse model of HCV-associated HCC. For young mice ages 3-12 months, there was no significant difference in the levels of hydroperoxides of phosphatidylcholine (PCOOH) and phosphatidylethanolamine in liver tissue homogenates between transgenic and nontransgenic control mice. In contrast, the PCOOH level was increased by 180% in old core gene transgenic mice > 16 months old. Concurrently, there was a significant increase in the catalase activity, and there were decreases in the levels of total and reduced glutathione in the same mice. A direct in situ determination by chemiluminescence revealed an increase in hydroperoxide products by 170% even in young transgenic mice, suggesting that hydroperoxides were overproduced but immediately removed by an activated scavenger system in young mice. Electron microscopy revealed lipofuscin granules, secondary lysosomes carrying various cytoplasmic organelles, and disruption of the double membrane structure of mitochondria, and PCR analysis disclosed a deletion in mitochondrial DNA. Interestingly, alcohol caused a marked increase in the PCOOH level in transgenic mice, suggesting synergism between alcohol and HCV in hepatocarcinogenesis. The HCV core protein thus alters the oxidant/antioxidant state in the liver in the absence of inflammation and may thereby contribute to or facilitate, at least in part, the development of HCC in HCV infection.
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PMID:Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. 1138 61

Liver steatosis, which involves accumulation of intracytoplasmic lipid droplets, is characteristic of hepatitis C virus (HCV) infection. By use of an in vivo transgenic murine model, we demonstrate that hepatic overexpression of HCV core protein interferes with the hepatic assembly and secretion of triglyceride-rich very low density lipoproteins (VLDL). Core expression led to reduction in microsomal triglyceride transfer protein (MTP) activity and in the particle size of nascent hepatic VLDL without affecting accumulation of MTP and protein disulfide isomerase. Hepatic human apolipoprotein AII (apo AII) expression in double-core/apo AII transgenic mice diminished intrahepatic core protein accumulation and abrogated its effects on VLDL production. Apo AII and HCV core colocalized in human HCV-infected liver biopsies, thus testifying to the relevance of this interaction in productive HCV infection. Our results lead us to propose a new pathophysiological animal model for induction of viral-related steatosis whereby the core protein of HCV targets microsomal triglyceride transfer protein activity and modifies hepatic VLDL assembly and secretion.
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PMID:Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. 1181 66

Hepatic steatosis and hepatocellular carcinoma (HCC) are common and serious features of hepatitis C virus (HCV) infection, and the core protein has been shown to play distinct roles in the pathogenesis. Here we report the direct interaction of HCV core protein with retinoid X receptor alpha (RXRalpha), a transcriptional regulator that controls many aspects of cell proliferation, differentiation, and lipid metabolism. The core protein binds to the DNA-binding domain of RXRalpha, leading to increase the DNA binding of RXRalpha to its responsive element. In addition, RXRalpha is activated in cells expressing the core protein as well as in the livers of the core-transgenic mice that would develop hepatic steatosis and HCC later in their lives. Using promoter genes of cellular retinol binding protein II (CRBPII) and acyl-CoA oxidase as reporters, we also show that the expression of the core protein enhances the transcriptional activity regulated by the RXRalpha homodimer as well as by the heterodimer with peroxisome proliferator activated receptor alpha. Furthermore, expression of the CRBPII gene is also up-regulated in the livers of HCV core-transgenic mice. In conclusion, these results suggest that modulation of RXRalpha-controlled gene expression via interaction with the core protein contributes to the pathogenesis of HCV infection.
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PMID:Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. 1191 42

Although hepatitis C virus (HCV) is a well-known causative agent of hepatocellular carcinoma (HCC), the mechanism by which HCV induces HCC remains obscure. To elucidate the role of HCV in hepatocarcinogenesis, a model of hepatocyte injury was established using HCV core transgenic mice, which were developed using C57BL/6 mice transfected with the HCV core gene under control of the serum amyloid P component promoter. After 18-24 months, neither steatosis nor hepatic tumors were found in transgenic mice. The extent of hepatocyte injury and tumorigenesis were then examined in transgenic mice following repeated administration of carbon tetrachloride (CCl(4)) using various protocols (20%, 1/week; 10%, 2/week and 20%, 2/week). Serum alanine aminotransferase (ALT) levels did not differ among HCV core transgenic mice and non-transgenic littermates; however, after 40 weeks, hepatic adenomas preferentially developed in transgenic mice receiving 20% CCl(4) once weekly. Moreover, HCC was observed in transgenic mice receiving 2 weekly injections of a 20% solution of CCl(4), and was not observed in the non-transgenic control mice. In conclusion, the HCV core protein did not promote hepatic steatosis or tumor development in the absence of hepatotoxicity. However, the HCV core protein promoted adenoma and HCC development in transgenic mice following repeated CCl(4) administration. These results suggest that hepatotoxicity resulting in an increased rate of hepatocyte regeneration enhances hepatocarcinogenesis in HCV-infected livers. Furthermore, this experimental mouse model provides a valuable method with which to investigate hepatocarcinogenesis.
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PMID:Repeated hepatocyte injury promotes hepatic tumorigenesis in hepatitis C virus transgenic mice. 1290 92

The mechanism by which the hepatitis C virus (HCV) causes chronic, progressive liver damage is unknown. Factors other than the virus itself have been implicated. The role of liver steatosis has been recently studied. Hepatic steatosis is a common histological finding occurring in more 50% of patients with chronic hepatitis C. Both host and viral factors have been demonstrated to play an important role in its development. In those patients infected with genotype 1, steatosis appears to be due to the co-existence of Non-Alchoholic SteatoHepatitis (NASH) with HCV and associated with an increased body mass index (BMI). Some recent observations suggest that steatosis may be of viral origin and related to genotype 3. This fact raises the possibility of a direct effect of specific viral sequences on the pathogenesis of lipid accumulation. Furthermore, hepatic steatosis attributed to genotype 3 correlates directly with serum and intrahepatic titters of HCV RNA. The resolution of steatosis after successful antiviral therapy as well as steatosis being a sign of recurrent HCV infection in patients with genotype 3 add convincing evidence that steatosis is viral related. The pathogenic mechanism induced by genotype 3 is speculative. A correlation between steatosis, intrahepatic HCV RNA and core protein expression suggest a direct effect. Further support is provided by the finding that HCV core protein induces steatosis in transgenic mice. Another possibility relates to interaction with hepatic triglyceride turnover. In conclusion, for patients infected with genotype 1, BMI has a role in the pathogenesis of steatosis while in those infected with genotype 3, steatosis may be due to a virus-specific cytopathic effect. Regardless of etiology, the contribution of both to liver fibrosis progression seems accepted.
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PMID:Hepatitis C virus infection and liver steatosis. 1463 8

Persistent infection of hepatitis C virus (HCV) can lead to a high risk for hepatocellular carcinoma(HCC). HCV core protein plays important roles in HCV-induced hepatocarcinogenesis, because its expression in mice causes hepatic steatosis and HCC without accompanying hepatitis. However, its precise mechanisms remain unclear. We investigated whether the HCV core protein alters the expression of the factors associated with hepatic steatosis and HCC in vivo. By Western immunoblot and Northern blot analyses, expression of the proteins including fatty acid-metabolizing enzymes and cell cycle regulators, which are induced by the activation of peroxisome proliferator-activated receptor alpha (PPARalpha), significantly increased in HCV core protein transgenic mice. This result suggests the possibility that PPARalpha activation might contribute to HCV core protein-mediated hepatocarcinogenesis.
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PMID:[Possible mechanisms of hepatitis C virus-related hepatocarcinogenesis]. 1555


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