Role of seipin in lipid droplet morphology and hepatitis C virus life cycle

Clément, Sophie; Fauvelle, Catherine; Branche, Emilie; Kaddai, Vincent; Conzelmann, Stéphanie; Boldanova, Tujana; Bartosch, Birke; Minehira, Kaori; Negro, Francesco

doi:10.1099/vir.0.054593-0

Cited by 10 publications

(13 citation statements)

References 35 publications

(43 reference statements)

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“…VSV-Gpp entry was evaluated as control. Control pseudoparticles were generated with the VSV-G glycoprotein46. Forty-eight hours post-transduction luciferase assay was performed using the Dual-Luciferase assay system kit (Promega) according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

Effect of Quercetin on Hepatitis C Virus Life Cycle: From Viral to Host Targets

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Clément

et al. 2016

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Quercetin is a natural flavonoid, which has been shown to have anti hepatitis C virus (HCV) properties. However, the exact mechanisms whereby quercetin impacts the HCV life cycle are not fully understood. We assessed the effect of quercetin on different steps of the HCV life cycle in Huh-7.5 cells and primary human hepatocytes (PHH) infected with HCVcc. In both cell types, quercetin significantly decreased i) the viral genome replication; ii) the production of infectious HCV particles and iii) the specific infectivity of the newly produced viral particles (by 85% and 92%, Huh7.5 and PHH respectively). In addition, when applied directly on HCV particles, quercetin reduced their infectivity by 65%, suggesting that it affects the virion integrity. Interestingly, the HCV-induced up-regulation of diacylglycerol acyltransferase (DGAT) and the typical localization of the HCV core protein to the surface of lipid droplets, known to be mediated by DGAT, were both prevented by quercetin. In conclusion, quercetin appears to have direct and host-mediated antiviral effects against HCV.

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Section: Methodsmentioning

confidence: 99%

Effect of Quercetin on Hepatitis C Virus Life Cycle: From Viral to Host Targets

Rojas

Campo

Clément

et al. 2016

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“…Conclusion: The TM6SF2 E167K substitution promotes steatosis and lipid abnormalities in part by altering TM6SF2 and microsomal triglyceride transfer protein expression and differentially impacts CHC and chronic hepatitis B viral load, while effects on fibrosis are marginal. (HEPATOLOGY 2016;64: [34][35][36][37][38][39][40][41][42][43][44][45][46] E ctopic lipid accumulation associated with the increasing worldwide prevalence of obesity (1) is linked with tissue meta-inflammation, (2) resulting in organ dysfunction, excess morbidity, and mortality. (3) In this context, hepatic rather than visceral fat deposition is more tightly linked with the metabolic complications of obesity, (4) and it is therefore not surprising that steatosis is now the most commonly observed histological abnormality across a spectrum of liver diseases.…”

Section: International Liver Disease Genetics Consortiummentioning

confidence: 99%

Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes

et al. 2016

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A genome-wide exome association study has identified the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 variant encoding an E167K substitution as a genetic determinant of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). The roles of this variant across a spectrum of liver diseases and pathologies and on serum lipids comparing viral hepatitis to NAFLD and viral load in chronic viral hepatitis, as well as its intrahepatic molecular signature, have not been well characterized. We undertook detailed analyses in 3260 subjects with viral and nonviral liver diseases and in healthy controls. Serum inflammatory markers and hepatic expression of TM6SF2 and genes regulating lipid metabolism were assessed in a subset with chronic hepatitis C (CHC). The rs58542926 T allele was more prevalent in 502 NAFLD patients than controls (P 5 0.02) but not different in cohorts with CHC (n 5 2023) and chronic hepatitis B (n 5 507). The T allele was associated with alterations in serum lipids and hepatic steatosis in all diseases and with reduced hepatic TM6SF2 and microsomal triglyceride transfer protein expression. Interestingly, the substitution was associated with reduced CHC viral load but increased hepatitis B virus DNA. The rs58542926 T allele had no effect on inflammation, impacted F2 fibrosis in CHC and NAFLD assessed cross-sectionally (odds ratio 5 1.39, 95% confidence interval 1.04-1.87, and odds ratio 5 1.62, 95% confidence interval 1.03-2.52, respectively; P < 0.03 for both), but had no effect on fibrosis progression in 1174 patients with CHC and a known duration of infection. Conclusion: The TM6SF2 E167K substitution promotes steatosis and lipid abnormalities in part by altering TM6SF2 and microsomal triglyceride transfer protein expression and differentially impacts CHC and chronic hepatitis B viral load, while effects on fibrosis are marginal. (HEPATOLOGY 2016;64:34-46)

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“…At present, no predictor of relapse to therapy with sofosbuvir has been identified, but the role of steatosis should not be dismissed altogether. Recent, experimental data show that the appearance of large lipid droplets in the cytoplasm of infected hepatocytes reduces intracellular HCV RNA level and virion production . This suggests that steatosis may represent a hitherto unrecognized mechanism of viral attenuation, possibly leading to a reduced immune clearance of infected hepatocytes.…”

Section: Hcv Genotype 3 and Response To Antiviral Therapymentioning

confidence: 99%

“…Recent, experimental data show that the appearance of large lipid droplets in the cytoplasm of infected hepatocytes reduces intracellular HCV RNA level and virion production. 71 This suggests that steatosis may represent a hitherto unrecognized mechanism of viral attenuation, possibly leading to a reduced immune clearance of infected hepatocytes. Whether this accounts for a persisting, low-level genotype 3 infection of hepatocytes under therapy predisposing to virological relapse after treatment withdrawal remains to be proven.…”

Section: Response To Pegylated Interferon-a and Ribavirinmentioning

confidence: 99%

Is genotype 3 of the hepatitis C virus the new villain?

2014

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Genotype 3 of the hepatitis C virus (HCV) has been long considered an easy-to-treat infection, with higher cure rates ( 70%) than other viral genotypes with the standard combination of pegylated interferon-a and ribavirin. However, the relative insensitivity of this genotype to most protease inhibitors and the recent unexpected data on decreased effectiveness of sofosbuvir have raised questions on how to achieve universal cure, a goal that seems reasonable for other genotypes. In addition, increasing clinical and experimental data show that HCV genotype 3 may be associated not only with severe steatosis, but also with accelerated fibrosis progression rate and increased oncogenesis. Conclusion: Currently available data suggest that we should increase our efforts to understand the virology and pathogenesis of HCV genotype 3, aiming at better and more potent, genotype-targeted treatments. (HEPATOLOGY 2014;59:2403-2412 A pproximately 185 million people are infected worldwide with the hepatitis C virus (HCV). 1 HCV is a major human pathogen causing progressive liver damage, culminating in cirrhosis and hepatocellular carcinoma (HCC), and various extrahepatic complications, ranging from type 2 diabetes to cardiovascular disorders. 2 HCV has a positive singlestranded RNA genome, characterized by a high heterogeneity, leading to classification of HCV isolates in at least seven genotypes and several subtypes. 3,4 Genotype 1 is the most prevalent genotype worldwide, accounting for 60% of the global infections, with a higher proportion of subtype 1b in Europe and 1a in the USA. Genotype 2 is found in the Mediterranean region and in some parts of Africa and the Americas. Genotype 3 is highly prevalent in the European population of intravenous drug users, and in a large proportion of patients-irrespective of risk factor-in Southern Asia. Overall, it is estimated that about 10-15% of the world HCV reservoir is accounted for by genotype 3. 5 Genotype 4 is the most prevalent type in the Middle East and in sub-Saharan Africa, and has spread to a significant proportion of infected persons across Europe, especially in drug users. Genotypes 5 and 6 are rare and concentrated in isolated clusters in France, Belgium, Syria, and Southern Africa. 6 The novel genotype 7 was identified in rare patients from Canada and Belgium, possibly infected in Central Africa. 4 The identification of HCV genotypes and subtypes is of obvious epidemiological interest. In addition, genotyping is critical to select the type and duration of antiviral therapy, due to a different response to antiviral therapy. Thus, genotype 1 has been considered, until now, the most difficult to treat genotype, with sustained virological response (SVR) rates of 50% with a dual therapy based on the combination of pegylated interferon-a and ribavirin, 7-9 only recently increasing to 70% with the addition of a protease inhibitor. 10,11 Dual therapy reaches higher SVR rates in genotypes 2 and 3 ( 70-80%) and intermediate rates in patients with genotype 4. Finally, some viral gen...

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Role of seipin in lipid droplet morphology and hepatitis C virus life cycle

Cited by 10 publications

References 35 publications

Effect of Quercetin on Hepatitis C Virus Life Cycle: From Viral to Host Targets

Effect of Quercetin on Hepatitis C Virus Life Cycle: From Viral to Host Targets

Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes

Is genotype 3 of the hepatitis C virus the new villain?

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