The interaction between HCV and nuclear receptor-mediated pathways

Raglow, Zoe; Thoma-Perry, Carly; Gilroy, Richard; Wan, Yu‐Jui Yvonne

doi:10.1016/j.pharmthera.2011.05.005

Cited by 6 publications

(9 citation statements)

References 112 publications

(171 reference statements)

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“…Functionally, CRYM was very recently reported in mice on high-fat-diet to be linked to modulation of nuclear receptor PPARγ activity, which has previously been shown to also affect HCV replication [94]. However, reports are divergent as to whether PPARγ acts in a pro-or anti-viral manner in HCV [24]. It should be noted that C-terminally FLAG-tagged variants of both, LBHD1 and CRYM, failed to reproduce the effect on HCV replication; however, as the N-terminally HA-tagged versions showed robust and reproducible effects in two different HCV genotypes, we assume the C-terminal tag might interfere with proper protein function or with important protein-protein interactions.…”

Section: Discussionmentioning

confidence: 99%

“…As described above, PPARγ activation has been implicated with HCV replication, but literature reports are not entirely coherent. Recently, other nuclear receptors have also been shown to be dysregulated in HCV infection and partially usurped by the virus, e.g., PPARα, LXR, RXR and FXR [18,24]. Particularly FXR also has a strong link to NR0B2, acting upstream of it and inducing its expression as part of a negative feedback loop in the bile acid metabolism in liver cells; while FXR gets activated by bile acids, NR0B2 inhibits bile acid synthesis (see Figure 8A) [79,80].…”

Section: Discussionmentioning

confidence: 99%

“…HCV hijacks many cellular pathways to establish and maintain a productive infection, e.g., autophagy [16] as well as glucose [17][18][19][20] and cholesterol metabolism [21,22]. Recent evidence implies that nuclear receptors contribute to mediating these changes and are, thus, important players during HCV infection [18,23,24].…”

Section: Introductionmentioning

confidence: 99%

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Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

Dächert

Gladilin

Binder

2019

Viruses

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Chronic Hepatitis C virus (HCV) infection still constitutes a major global health problem with almost half a million deaths per year. To date, the human hepatoma cell line Huh7 and its derivatives is the only cell line that robustly replicates HCV. However, even different subclones and passages of this single cell line exhibit tremendous differences in HCV replication efficiency. By comparative gene expression profiling using a multi-pronged correlation analysis across eight different Huh7 variants, we identified 34 candidate host factors possibly affecting HCV permissiveness. For seven of the candidates, we could show by knock-down studies their implication in HCV replication. Notably, for at least four of them, we furthermore found that overexpression boosted HCV replication in lowly permissive Huh7 cells, most prominently for the histone-binding transcriptional repressor THAP7 and the nuclear receptor NR0B2. For NR0B2, our results suggest a finely balanced expression optimum reached in highly permissive Huh7 cells, with even higher levels leading to a nearly complete breakdown of HCV replication, likely due to a dysregulation of bile acid and cholesterol metabolism. Our unbiased expression-profiling approach, hence, led to the identification of four host cellular genes that contribute to HCV permissiveness in Huh7 cells. These findings add to an improved understanding of the molecular underpinnings of the strict host cell tropism of HCV.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

Dächert

Gladilin

Binder

2019

Viruses

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“…With its capacity to establish persistent, lifelong infection, HCV has been identified as an effective combatant of the host antiviral immune response (Choo et al, 1989). Like many other RNA viruses, HCV has developed strategies to impair the host's antiviral type I IFN response (Raglow et al, 2011). In chronically HCV-infected patients, Th1 and cytotoxic responses are decreased in the liver and peripheral blood (Thimme et al, 2001).…”

Section: Hepatitis C Virusmentioning

confidence: 99%

SOCS proteins in infectious diseases of mammals

Delgado-Ortega

Marc

Dupont

et al. 2013

Veterinary Immunology and Immunopathology

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As for most biological processes, the immune response to microbial infections has to be tightly controlled to remain beneficial for the host. Inflammation is one of the major consequences of the host's immune response. For its orchestration, this process requires a fine-tuned interplay between interleukins, endothelial cells and various types of recruited immune cells. Suppressors of cytokine signalling (SOCS) proteins are crucially involved in the complex control of the inflammatory response through their actions on various signalling pathways including the JAK/STAT and NF-κB pathways. Due to their cytokine regulatory functions, they are frequent targets for exploitation by infectious agents trying to escape the host's immune response. This review article aims to summarize our current knowledge regarding SOCS family members in the different mammalian species studied so far, and to display their complex molecular interactions with microbial pathogens.

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“…An intriguing feature of HCV infection is its relationship with lipids, as indicated by the following: (1) HCV virions circulate in serum bound to lipoproteins, called lipoviroparticles;9 (2) steatosis is prevalent in HCV‐infected patients;10, 11 and (3) lipids are essential for the HCV life cycle and the virus was named a “metabolovirus.”12, 13 Nuclear receptors, which are transcriptional factors, play pivotal roles in lipid homeostasis. In addition, nuclear receptors also play important roles in regulating inflammatory response and fibrogenesis 13–15. HCV infection is associated with changes in nuclear receptor‐mediated signaling.…”

mentioning

confidence: 99%

Alteration of hepatic nuclear receptor-mediated signaling pathways in hepatitis C virus patients with and without a history of alcohol drinking

Gilroy

Taylor

et al. 2011

Hepatology

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The current study tests a hypothesis that nuclear receptor signaling is altered in chronic hepatitis C patients and that the altered pattern is alcohol drinking history specific. The expression of a panel of more than 100 genes encoding nuclear receptors, co-regulators, and their direct/indirect targets was studied in human livers. (1) Gene expression pattern was compared between 15 normal donor livers and 23 HCV genotype 1 positive livers from patients without a drinking history (age, gender, and BMI matched). HCV infection increased the expression of nuclear receptors small heterodimer partner and constitutive androstane receptor (CAR) as well as genes involved in fatty acid trafficking, bile acid synthesis and uptake, and inflammatory response. However, the expression of retinoid x receptor (RXR) α, peroxisomal proliferator activated receptor (PPAR) α and β as well as SREBP-1c was decreased in HCV-infected livers. (2) Gene expression pattern was compared in chronic hepatitis C patients with (21) and without (13) a drinking history. Alcohol drinking increased the expression of genes involved in fatty acid uptake, trafficking, and oxidation, but decreased the expression of genes responsible for gluconeogenesis. These changes were consistent with reduced fasting plasma glucose levels and altered expression of upstream regulators that include RXRα, PPARα, and CAR. (3) The mRNA levels of fibroblast growth factor 21, IL-10, and fatty acid synthase, which are all regulated by nuclear receptors, showed independent correlation with hepatic HCV RNA levels. Our findings suggest that those genes and pathways that showed altered expression could potentially be therapeutic targets for HCV infection and/or alcohol drinking-induced liver injury.

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The interaction between HCV and nuclear receptor-mediated pathways

Cited by 6 publications

References 112 publications

Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

SOCS proteins in infectious diseases of mammals

Alteration of hepatic nuclear receptor-mediated signaling pathways in hepatitis C virus patients with and without a history of alcohol drinking

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