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

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

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

Taken together, our results suggest that HCV infection suppresses GLUT2 transcription via downregulation of HNF-1␣ expression at both transcriptional and translational levels (Fig. 8). We demonstrated that HNF-1␣ protein levels were greatly re- duced compared to the reduced levels of HNF-1 ␣ mRNA. We demonstrated that pepstatin A, but not E64-d, restored the levels of HNF-1 ␣ protein, suggesting that an aspartic protease is in- volved in the degradation of HNF-1␣ protein. Pepstatin A is widely used for investigation of autophagy and lysosomal degra- dation. Further studies are needed to elucidate how HCV induces lysosomal degradation of HNF-1 ␣ protein and how HNF-1␣ pro- tein is selectively downregulated by HCV infection. Our data sug- gest that the HCV NS5A protein is responsible for the HCV-in- duced degradation of HNF-1␣ protein. Using a panel of NS5A deletion mutants, we demonstrated that domain I of NS5A is im- portant for association with HNF-1␣ protein. NS5A domain I is relatively conserved among HCV genotypes compared to do- mains II and III, suggesting that NS5A–HNF-1␣ interaction is common to all the HCV genotypes. Domain I coordinates a single zinc atom per protein molecule and is essential for HCV RNA replication (35). The crystal structure of NS5A domain I revealed the presence of a zinc coordination motif and a C-terminal disul- fide bond (36). NS5A domain I was found to bind many host proteins, RNA, and membranes (16). It is possible that physical interaction between NS5A protein and HNF-1 ␣ protein is impor- tant for selective degradation of HNF-1␣ protein. One possible mechanism is that NS5A protein may recruit HNF-1 ␣ protein to the lysosome. Further study is necessary to test this possibility.
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Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment in the gut epithelium

Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment in the gut epithelium

Inactivation of Notch signalling resulted in the complete loss of proliferating crypt progenitors and their conversion into postmitotic goblet cells (van Es et al., 2005b). The molecular mechanisms of this conversion were recently elucidated. Notch-mediated Hes1 expression contributes to the maintenance of the proliferative crypt compartment of the small intestine by inhibiting the transcription of two cyclin-dependent kinase inhibitors (Riccio et al., 2008). Gain-of- function studies also demonstrated that Notch activity is required for the maintenance of proliferating crypt cells in the intestinal epithelium (Fre et al., 2005). Interestingly, we showed that Hnf1a and b can activate directly the expression of Jag1, a gene that encodes for a ligand of the Notch pathway and whose genomic sequence contains Hnf1 binding sites conserved throughout evolution that are bound by both Hnf1a and Hnf1b. In line with this observation, the expression of several effectors directly activated by Notch signalling, including Hes1, Hes5 and Hes6, was downregulated in the double mutants. This should explain why our double-mutant mice had a slight, but significant, increased number of goblet cells, which could be ascribed to the specific downregulation of Notch signalling activity. One of the key genes controlling secretory cell lineage commitment is Atoh1.
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Inhibition of Hepatitis B Virus Gene Expression and Replication by Hepatocyte Nuclear Factor 6

Inhibition of Hepatitis B Virus Gene Expression and Replication by Hepatocyte Nuclear Factor 6

HNF6 reduces the steady-state levels of HBV RNA via post- transcriptional mechanisms. The pgRNA of HBV serves as the template for reverse transcription and is critical for viral replica- tion. The transcription of pgRNA is controlled by the EnhI/X and EnhII/C promoters. Since HNF6 does not influence the activity of these two elements (Fig. 4A), we sought to clarify whether the intrinsic promoters of HBV are required for the inhibition by HNF6. To this end, we generated three constructs (pSV-HBV, pSV-2.4, and pSV-2.1) in which the pgRNA, 2.4-kb RNA, and 2.1-kb RNA of HBV are transcribed under the control of the sim- ian virus 40 (SV40) promoter, as depicted in Fig. 6A. These three constructs were transfected into HepG2 cells along with HNF6 or its control vector. As shown in Fig. 6B, the levels of HBV RNA transcribed from SV40 promoters were also dramatically inhib- ited by HNF6. To exclude the possibility that HNF6 might affect the activity of SV40 promoter directly, a construct in which the
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Hepatocyte Nuclear Factor 4α and Downstream Secreted Phospholipase A2 GXIIB Regulate Production of Infectious Hepatitis C Virus

Hepatocyte Nuclear Factor 4α and Downstream Secreted Phospholipase A2 GXIIB Regulate Production of Infectious Hepatitis C Virus

HNF4 ␣ downregulation resulted in rearrangement of cytosolic lipid droplets (LDs), as evidenced by the aggregation of large LDs and distorted cytosolic distribution. Phospholipase A 2 GXIIB (PLA 2 GXIIB), an HNF4 ␣-regulated factor involved in VLDL secre- tion, was found to be crucial in HCV secretion. PLA 2 GXIIB expression was upregulated in hepatocytes harboring HCV sub- genomic replicons or in HCV-infected hepatocytes. This upregulation was transcriptionally controlled in an HNF4␣-dependent manner after HCV infection. Furthermore, PLA 2 GXIIB combined with microsomal triglyceride transfer protein was found to be responsible for the regulation of HNF4 ␣-induced HCV infectivity. These results suggest that HNF4␣ and its downstream PLA 2 GXIIB are important factors affecting the late stage of the HCV life cycle and may serve as potential drug targets for the treatment of HCV infection.
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Suppression of Hepatocyte Nuclear Factor 4 Alpha by Long-Term Infection of Hepatitis B Virus Contributes to Tumor Cell Proliferation

Suppression of Hepatocyte Nuclear Factor 4 Alpha by Long-Term Infection of Hepatitis B Virus Contributes to Tumor Cell Proliferation

In this report, we demonstrated that HBV-induced downregulation of HNF4α could enhance the proliferation of hepatoma cells and increase their tumorigenicity both in vitro and in vivo. Of note, HNF4a recovery through pharmacological or genetical approach, greatly contributed to the inhibition of cell proliferation. Moreover, our results clearly revealed the substantial efficacy of HBV expression on liver tumor progression in animal models. Therefore, HBV mediated downregulation of HNF4a plays considerable role in the HBV related carcinogenesis. Although others have shown that HBx activates signals that can diminish the overall level of HBV replication in order to balance cell survival [14], in long-term HBV infection, we showed considerable reduction in HNF4α level attained by HBx to elevate cell proliferation and tumor progress.
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The hepatitis E virus ORF3 protein regulates the expression of liver-specific genes by modulating localization of hepatocyte nuclear factor 4

The hepatitis E virus ORF3 protein regulates the expression of liver-specific genes by modulating localization of hepatocyte nuclear factor 4

The HNF4 transcription factor is expressed mainly in the liver and plays important roles in nutrient transport and metabolism, blood maintenance, immune function, liver differentiation and expression of growth factors [18,19,20]. The HNF4 protein is expressed early in embryonic life, long before liver development and mice deleted for this gene die in utero between days 9.5-10.5, and exhibit impaired gastrulation [20]. In the adult liver, HNF4 is required for its proper function. Other hepatotropic viruses like HBV and HCV also modulate HNF4 for their efficient replication and pathogenesis [34,35]. An earlier study from our group also found lower plasma levels of albumin and transthyretin in HEV infected patients [36]; the genes for these are major targets of HNF4. On transcriptional analysis, several of the down regulated genes were found to be regulated by HNF4, and this was also observed in nuclear levels of the HNF4 protein. Our microscopy data clearly proved that in a replicon expression model as well as in a virus infection system, pORF3 modulated the nuclear localization of HNF4. A recent report suggested that phosphor- ylation of a highly conserved serine (Ser78) in HNF4 resulted in its impaired nuclear localization [21], and HNF4 activity was dependent upon ERK and Akt kinases [22,23]. Our previous studies have shown that ERK and Akt are also activated in ORF3- expressing cells [10,12]. To test for these alternative pathways, we used the hydrophobic domain 1 deleted pORF3 which is unable to activate ERK and the pharmacological inhibitor LY294002 that blocks Akt activation, and found that this inhibition significantly reduces pORF3-mediated phosphorylation of HNF4. However, blocking of either pathway alone was not sufficient to completely revert this effect. Our results indicate that pORF3 regulates several hepatotropic proteins by inducing the phosphorylation of HNF4, which would in turn reduce its translocation to the nucleus and attenuate its transcription factor activity.
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Regulation of Hepatocyte Nuclear Factor 1 Activity by Wild-Type and Mutant Hepatitis B Virus X Proteins

Regulation of Hepatocyte Nuclear Factor 1 Activity by Wild-Type and Mutant Hepatitis B Virus X Proteins

Department of Molecular Microbiology and Immunology, Keck School of Medicine, 1 and Department of Pharmaceutical Sciences, School of Pharmacy, 2 University of Southern California, Los Angeles, California 90033 Received 14 September 2001/Accepted 14 March 2002 The hepatitis B virus (HBV) core promoter regulates the transcription of two related RNA products named precore RNA and core RNA. Previous studies indicate that a double-nucleotide mutation that occurs frequently during chronic HBV infection converts a nuclear receptor binding site in the core promoter to the binding site of the transcription factor hepatocyte nuclear factor-1 (HNF-1) and specifically suppresses the transcription of the precore RNA. This mutation also changes two codons in the overlapping X protein coding sequence. In this report, we demonstrate that the X protein and its mutant X mt can physically bind to HNF-1 both in vitro and in vivo. Further analyses indicate that both X and X mt can enhance the gene transactivation and the DNA binding activities of HNF-1. This finding demonstrates for the first time that the X protein can stimulate the DNA binding activity of a homeodomain transcription factor. Interestingly, while both X and X mt can stimulate the HNF-1 activities, they differ in their effects: a smaller amount of X mt is needed to generate greater transactivation and DNA binding activities of HNF-1. This functional difference between X and X mt may have important implications in HBV pathogenesis and is apparently why they have different effects on the core promoter bearing the HNF-1 binding site.
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Regulation of transcription from the hepatitis B virus large surface antigen promoter by hepatocyte nuclear factor 3.

Regulation of transcription from the hepatitis B virus large surface antigen promoter by hepatocyte nuclear factor 3.

of these two factors presumably explains the highly restricted expression of the 2.4-kb HBV transcript to the liver. It is likely that the level of synthesis of the various HBV RNAs is coordinately regulated so that the correct levels of viral products are produced to permit viral biosynthesis to occur efficiently. In this regard, the observation that an impor- tant regulatory element (CpE) of the nucleocapsid promoter (54) also binds HNF3 transcription factors (Fig. 2) (17) sug- gests that this family of liver-enriched transcription factors might also serve a role in coordinately regulating the level of the 3.5- and 2.4-kb viral RNAs. However, it is clear that the magnitude of the effect of HNF3 on the level of transcription from the large surface antigen and nucleocapsid promoters is very different, at least in the transient-transfection analysis in HepG2.1 cells (Table 1). Recently, it has been observed that HBV enhancer I possesses an HNF3-binding site (9, 35). It appears that the HNF3 site in the enhancer I sequence can modulate the level of transcription in the context of the herpes simplex virus thymidine kinase promoter (9). However, in our study, exogenously expressed HNF3 does not stimulate tran- scription from any of the HBV promoters in the context of the complete viral genome by interacting with the enhancer I se- quence, except possibly the nucleocapsid promoter. In con- trast, HNF3 dramatically increases the level of transcription from the large surface antigen promoter in the absence of enhancer I sequences (Table 1; Fig. 3). This suggests that the transcriptional potential of the enhancer I HNF3 site can be observed only in transient-transfection analysis when the en- hancer I sequence is removed from the context of the HBV genome. Despite the fact that the HNF3 transcription factors appear to influence the level of expression from the HBV promoters differentially in transient-transfection analysis, it seems likely that these transcription factors play some role in the coordinate regulation of the level of expression from the enhancer I/X gene, nucleocapsid, and large surface antigen promoters during viral infection.
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Hepatitis C Virus NS5A Protein Promotes the Lysosomal Degradation of Hepatocyte Nuclear Factor 1α via Chaperone-Mediated Autophagy

Hepatitis C Virus NS5A Protein Promotes the Lysosomal Degradation of Hepatocyte Nuclear Factor 1α via Chaperone-Mediated Autophagy

ACKNOWLEDGMENTS We are grateful to C. M. Rice (Rockefeller University, New York, NY) for providing us Huh-7.5 cells and pFL-J6/JFH1. We thank Y. Kozaki and Y. Sakahara for secretarial work. This research was supported by Basic and Clinical Research on Hepatitis from Japan Agency for Medical Research and Development, AMED, under grant numbers JP17fk0210304 and JP18fk0210040. This work was also supported in part by grants-in- aid from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Daiichisankyo, Astellas, and Hyogo Science and Technology Association. C.M. is supported by the Program for Promoting the Reform of National Universities of MEXT.
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Hepatocyte nuclear factor 1α suppresses steatosis associated liver cancer by inhibiting PPARγ transcription

Hepatocyte nuclear factor 1α suppresses steatosis associated liver cancer by inhibiting PPARγ transcription

J Clin Invest. 2017;127(5):1873-1888. https://doi.org/10.1172/JCI90327. Worldwide epidemics of metabolic diseases, including liver steatosis, are associated with an increased frequency of malignancies, showing the highest positive correlation for liver cancer. The heterogeneity of liver cancer represents a clinical challenge. In liver, the transcription factor PPARg promotes metabolic adaptations of lipogenesis and aerobic glycolysis under the control of Akt2 activity, but the role of PPARg in liver tumorigenesis is unknown. Here we have combined preclinical mouse models of liver cancer and genetic studies of a human liver biopsy atlas with the aim of identifying putative therapeutic targets in the context of liver steatosis and cancer. We have revealed a protumoral interaction of Akt2 signaling with hepatocyte nuclear factor 1a (HNF1a) and PPARg, transcription factors that are master regulators of hepatocyte and adipocyte differentiation, respectively. Akt2 phosphorylates and inhibits HNF1a, thus relieving the suppression of hepatic PPARg expression and promoting tumorigenesis. Finally, we observed that pharmacological inhibition of PPARg is therapeutically effective in a preclinical murine model of steatosis- associated liver cancer. Taken together, our studies in humans and mice reveal that Akt2 controls hepatic tumorigenesis through crosstalk between HNF1a and PPARg.
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Hepatitis C Virus Infection Upregulates CD55 Expression on the Hepatocyte Surface and Promotes Association with Virus Particles

Hepatitis C Virus Infection Upregulates CD55 Expression on the Hepatocyte Surface and Promotes Association with Virus Particles

CD55 limits excessive complement activation on the host cell surface by accelerating the decay of C3 convertases. In this study, we observed that hepatitis C virus (HCV) infection of hepatocytes or HCV core protein expression in transfected hepatocytes upregulated CD55 expression at the mRNA and protein levels. Further analysis suggested that the HCV core protein or full- length (FL) genome enhanced CD55 promoter activity in a luciferase-based assay, which was further augmented in the presence of interleukin-6. Mutation of the CREB or SP-1 binding site on the CD55 promoter impaired HCV core protein-mediated up- regulation of CD55. HCV-infected or core protein-transfected Huh7.5 cells displayed greater viability in the presence of CD81 and CD55 antibodies and complement. Biochemical analysis revealed that CD55 was associated with cell culture-grown HCV after purification by sucrose density gradient ultracentrifugation. Consistent with this, a polyclonal antibody to CD55 captured cell culture-grown HCV. Blocking antibodies against CD55 or virus envelope glycoproteins in the presence of normal human serum as a source of complement inhibited HCV infection. The inhibition was enhanced in the presence of both the antibodies and serum complement. Collectively, these results suggest that HCV induces and associates with a negative regulator of the com- plement pathway, a likely mechanism for immune evasion.
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Nuclear Covalently Closed Circular Viral Genomic DNA in the Liver of Hepatocyte Nuclear Factor 1α-Null Hepatitis B Virus Transgenic Mice

Nuclear Covalently Closed Circular Viral Genomic DNA in the Liver of Hepatocyte Nuclear Factor 1α-Null Hepatitis B Virus Transgenic Mice

7). These observations represent the first demonstration that the viral genome can cycle into the nucleus from the cytoplasm in this transgenic mouse model. This analysis demonstrates that HNF1␣ is an important in vivo regulator of viral replication but not viral transcription in the HBV transgenic mouse. Consequently, it appears possible that indirect effects on cellular gene expression rather than direct effects on viral gene expression can explain the HNF1␣- mediated alterations in HBV replication. Regardless of the mechanism responsible for the increase in replication, it is associated with the identification of two novel replication in- termediates that are not readily detectable in the HBV trans- genic mouse under normal physiological conditions. The pres- ence of protein-free RC HBV DNA in the cytoplasm and CCC HBV DNA in the nucleus indicates that cycling of viral repli- cation intermediates into the nucleus occurs in this in vivo model system. If the protein-free RC HBV DNA is a precursor of the nuclear CCC HBV DNA, these results suggest that the first event in translocating viral DNA to the nucleus is the removal of the terminal protein from the 5⬘ end of the minus strand of the HBV DNA in the cytoplasm. This intermediate is then translocated into the nucleus and converted to CCC DNA. The observation that nuclear CCC HBV DNA can be generated in this system suggests that it might be possible to examine the transcriptional properties of this molecule in vivo.
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Hepatocyte Nuclear Factor 3β Inhibits Hepatitis B Virus Replication In Vivo

Hepatocyte Nuclear Factor 3β Inhibits Hepatitis B Virus Replication In Vivo

ing HBV transgenic mice were compared with those of the control rat HNF3␤(⫺) HBV transgenic mice (Fig. 2, 4, and 5). As observed in cell culture (21, 22), elevated levels of HNF3␤ were associated with a modest decrease in the level of expres- sion of the two major HBV transcripts. This observation dem- onstrates that the negative effect of a specific transcription factor on HBV transcription and replication observed in cell culture can be recapitulated in vivo in the HBV transgenic mouse model system. The mechanism of HNF3␤-mediated inhibition of viral transcription in vivo probably does not in- volve decreasing HBV promoter activity, because HNF3 has been shown to activate the level of transcription from the nucleocapsid and large surface antigen promoters in reporter gene analysis (9, 15). In addition, elevated levels of HNF3␤ in transgenic mice are associated with increased levels of expres- sion of HNF3-responsive genes, such as the insulin-like growth factor binding protein 1 gene (16). Additional cell culture analysis with viral replication-competent genomes suggests HNF3␤ may reduce viral transcription by interfering with the transcriptional elongation step rather than affecting promoter activity (22).
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Intrahepatic Gene Expression during Chronic Hepatitis C Virus Infection in Chimpanzees

Intrahepatic Gene Expression during Chronic Hepatitis C Virus Infection in Chimpanzees

An understanding of the stimuli involved in ISG expression during HCV infection may help resolve the cell types involved as well. Infected hepatocytes are presumably the initial source of the ISG response, with dsRNA inducing transcription from ISREs; however, due to the potential inhibition of this pathway by viral proteins, it is not clear whether infected hepatocytes produce IFN- ␣ / ␤ in response to viral dsRNA. However, one can envision a scenario in which newly infected cells produce IFN- ␣ / ␤ before the levels of viral proteins accumulate to their critical inhibitory levels. A high level of cell turnover could provide newly infected hepatocytes even during the chronic infection. Dendritic cells may also be involved in IFN- ␣ pro- duction due to the interaction of dsRNA with Toll-like recep- tor 3. The magnitude of the ISG response is the only evidence for the production of type I IFN, since the type I IFN tran- scripts themselves do not increase significantly. However, if only a portion of hepatocytes are infected, and only newly infected hepatocytes express IFN- ␣ / ␤ prior to the accumula- tion of NS3 and/or NS5A, the lack of a significant increase in IFN transcripts over the baseline level in total liver RNA would not be surprising. A comparison of the viral load in both the serum and liver of chronically infected chimpanzees (Table 1) indicates that the ISG response is not proportional to the amount of viral RNA present in the liver at the time of biopsy (Fig. 2 and 6). In contrast, during acute infections, the ISG response increased and decreased as the viral RNA levels peaked and then declined. Although the present study was cross-sectional in nature, the abundance of viral RNA in the serum and liver of these animals has been remarkably consis- FIG. 6. ISG and cytokine gene expression as a function of viral load. The viral load in the livers of the 10 chronically infected animals in this study was plotted relative to the magnitude of expression changes in ISGs (ISG12 [ F ] and ISG15 [ ƒ ]) and cytokines (I-TAC [ ⽧ ], IP-10 [ Œ ], and midkine [■]). The viral RNA level in the liver is given as genome equivalents per microgram of total cell RNA.
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Expression of Regeneration and Tolerance Factor Correlates Directly with Human Immunodeficiency Virus Infection and Inversely with Hepatitis C Virus Infection

Expression of Regeneration and Tolerance Factor Correlates Directly with Human Immunodeficiency Virus Infection and Inversely with Hepatitis C Virus Infection

HCV ⫹ individuals, but not in those seropositive for HCV alone. This result indicates that there may be a correlation between RTF expression and HIV-associated immune activa- tion. Interestingly, as illustrated in Table 1, the percentage of CD8 ⫹ T cell subsets with CD38 that expressed RTF was sig- nificantly lower in HIV ⫹ HCV ⫹ individuals than in HIV ⫹ individuals. Thus, this may be a useful marker for distinguish- ing those seropositive for HIV alone from HIV ⫹ individuals coinfected with HCV or having another secondary infection.

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Studies of genetic variability of the hepatocyte nuclear factor-1α gene in an Indian maturity-onset diabetes of the young family

Studies of genetic variability of the hepatocyte nuclear factor-1α gene in an Indian maturity-onset diabetes of the young family

reduce transcriptional activity in vitro, lower glucose- stimulated insulin secretion in vivo, and increase the risk of type 2 diabetes especially in the overweighs and the elders. As we know, HNF- is biologically active in a dimer form. The I27L is located in the dimerization domain and may affect the function of the protein. Fur- thermore, Isoleucine at position 27 is conserved among human, rat and mouse and it is located between two known MODY3 mutations (G20R and G31D). Conser- vation among different species and the location of this polymorphism suggest the biologic importance of this amino acid. Although the I27L polymorphism is not the direct cause of MODY3, there is evidence suggesting the significant roles of I27L polymorphism in the pathogen- esis of diabetes. Here we report an Indian family though Table 1 The clinical characteristics of this family
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Mechanisms of Inhibition of Nuclear Hormone Receptor-Dependent Hepatitis B Virus Replication by Hepatocyte Nuclear Factor 3β

Mechanisms of Inhibition of Nuclear Hormone Receptor-Dependent Hepatitis B Virus Replication by Hepatocyte Nuclear Factor 3β

inhibited HBV replication but to a considerably lesser extent than from a template that encoded the HBeAg polypeptide. This analysis indicated that HBeAg contributes to the inhibi- tion of viral replication in mouse fibroblasts under certain circumstances. HNF3␤ mediates the inhibition of viral repli- cation partly by decreasing the level of precore RNA less than that of the pregenomic RNA and consequently decreasing the level of HBeAg less than that of the core polypeptide. If the HBeAg polypeptide can inhibit replication-competent capsid assembly from occurring as has been suggested (40), a greater decrease in core polypeptide synthesis than that in HBeAg synthesis could result in a larger than expected decrease in viral biosynthesis. However, alterations in the relative levels of the precore and pregenomic RNAs can account for only part of the HNF3␤-mediated inhibition of nuclear hormone receptor- mediated viral replication.
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Hepatitis C Virus Infection

Hepatitis C Virus Infection

Patients should meet certain criteria for thera- py. These include medical aspects of the disease, as well as its associated social considerations. The decision to treat must evaluate overall health, age, likelihood of response and compli- ance issues. On at least two occasions separated by three months, patients should have confirmed HCV infection with detectable serum HCV-PCR and elevated alanine aminotransferase (ALT)

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Hepatitis C Virus Infection

Hepatitis C Virus Infection

In 1994, the first outbreak of HCV infection asso- ciated with a licensed intravenous immunoglobulin was reported in the United States. 16,17 According to the US Public Health Service, this outbreak involved recipients of a single product, Gammagard, also called Polygam (Baxter Healthcare Corporation, Glendale, CA), received between April 1, 1993, and February 23, 1994, when this specific product was withdrawn from the market. Presently, Gammagard is processed by a solvent/detergent treatment, ren- dering it noninfectious for HCV. Similar outbreaks have been reported from other countries among re- cipients of products manufactured in Europe. 18 Intra- muscular immune globulin has not been associated with the transmission of any infectious disease in the United States. To ensure their safety, all immune globulin products that are currently available com- mercially in the United States must undergo an in- activation procedure or be HCV RNA-negative be- fore release.
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The impact of hepatocyte nuclear factor-1α on liver malignancies and cell stemness with metabolic consequences

The impact of hepatocyte nuclear factor-1α on liver malignancies and cell stemness with metabolic consequences

Though these proteins share similar DNA-binding charac- teristics, their activation domains are distinct. For the same reason, homodimers of HNF- and HNF-1β trigger the transcription, while heterodimers of these two proteins have a potential to block HNF--dependent genes as some isoforms of HNF-1β are deficient in activation domain. The plausible explanation behind functional diversity of HNF- and HNF-1β in hepatocellular carcinoma can be traced in their structural details. Today, it has been proved that HNF- shows protective behavior against cancer, while HNF-1β seems to promote tumorigenesis. Interestingly, monomers of both proteins exchange freely with each other to form homo- and heterodimers. This possibly explains the importance of immediate microenvironment in the liver and other organs that may or may not facilitate the tran- scriptional relationship between HNF- and HNF-1β.
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