Autophagy Protects Cells From HCV-Induced Defects in Lipid Metabolism

Vescovo, Tiziana; Romagnoli, Alessandra; Perdomo, Ariel Basulto; Corazzari, Marco; Ciccosanti, Fabiola; Alonzi, Tonino; Nardacci, Roberta; Ippolito, Giuseppe; Tripodi, Marco; García‐Monzón, Carmelo; Iacono, Oreste Lo; Piacentini, Mauro; Fimia, Gian María

doi:10.1053/j.gastro.2011.11.033

Cited by 67 publications

(66 citation statements)

References 69 publications

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“…We have subsequently shown that disruption of autophagy machinery in HCV-infected hepatocytes activates the interferon (IFN) signaling pathway, resulting in enhancement of the innate immune response (40). HCV-mediated autophagy also controls lipid production (48). However, how HCV induces autophagy remains poorly understood.…”

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confidence: 99%

Hepatitis C Virus Upregulates Beclin1 for Induction of Autophagy and Activates mTOR Signaling

Shrivastava

Chowdhury

Steele

et al. 2012

J Virol

155

122

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Hepatitis C virus (HCV) induces autophagosome formation in infected human hepatocytes. We have previously reported that HCV exploits autophagic machinery in favor of virus growth and survival in host cells (S. Shrivastava et al., Hepatology 53:406 -414, 2011); however, the mechanisms for autophagy induction is poorly understood. In the present study, we observed that HCV infection transcriptionally upregulates Beclin1, which forms complex with Vps34, the class III phosphatidylinositol 3-kinase, as a first step for autophagy initiation. Although Bcl-2 has an anti-autophagy effect by its association with Beclin1 in nutrient-deprived cells, our studies revealed that HCV-mediated autophagy occurs independent of Beclin1-Bcl-2 dissociation. Mammalian target of rapamycin (mTOR) is a positive regulator of cell growth and is recognized as an inhibitor of autophagy induction. Our results demonstrated that HCV infection enhances phospho-mTOR expression and its downstream target 4EBP1 activation, suggesting that mTOR is not a negative regulator of HCV-induced autophagy. On the other hand, HCV infection in autophagyimpaired cells reduced phospho-mTOR, mTOR, and phospho-4EBP1 expression. Together, these results suggested that HCV induces autophagy by upregulating Beclin1 and activates mTOR signaling pathway, which in turn may promote hepatocyte growth.

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confidence: 99%

Hepatitis C Virus Upregulates Beclin1 for Induction of Autophagy and Activates mTOR Signaling

Shrivastava

Chowdhury

Steele

et al. 2012

J Virol

155

122

View full text Add to dashboard Cite

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“…Limited studies with similar results evaluated autophagy in patients with chronic HCV infection [69,70]. However, in experimental studies autophagy was activated in HCV-RNA expressing cultured cells [71][72][73][74].…”

Section: Discussionmentioning

confidence: 99%

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

Lashen¹

2017

JLRDT

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Background: In chronic hepatitis C (CHC) infection, liver disease progression results from viral persistence. Deregulation of target of rapamycin (TOR) signaling and autophagy is detected in viral infections and cancer. We studied the role of TOR and autophagy in the progression of CHC infection.Methods: 54 patients infected with HCV, [27 with CHC; 13 with cirrhosis and 14 with hepatocellular carcinoma (HCC)]; and 15 healthy subjects were included. Quantification of serum TOR was determined using enzyme linked immunosorbent assay. Tissue samples were immune-stained using TOR and autophagy protein 5 (Atg5) polyclonal antibodies. Expression of TOR and Atg5 was scored semi-quantitatively.Results: Expression and serum TOR were higher in HCC patients compared to patients without HCC (P< 0.05). Serum and expression of TOR were positively correlated to inflammation, fibrosis, steatosis and tumor characteristics (Alpha-fetoprotein, maximum diameter, tumor grade and CLIP stage) (P<0.05). Expression of Atg5 was inversely correlated with inflammation, fibrosis and tumor characteristics (P<0.05), Atg5 showed significant inverse correlation with serum and intra-hepatic expression of TOR (P<0.05). Serum TOR showed high sensitivity and specificity in discriminating infected patients with and without HCC at a cut-off value of 4.55 ng/ml [Area under ROC curve = 0.970]. Conclusion:Activation of TOR plays an important role in progression of HCV related liver disease possibly though autophagy suppression and they could be a potential therapeutic target. Serum TOR is a potential seromarker in discriminating HCV infected patients with and without HCC with high sensitivity and specificity.

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“…In addition to AMPK inhibition, the increased expressions of sterol regulatory element-binding protein and fatty acid synthase, both important for intracellular lipid synthesis, are thought to enhance lipogenesis after HCV gains entry into cells (121,122). Lipid droplets, which serve as important organelles for HCV assembly (123), are also targeted for degradation by HCV-induced autophagy (124,125). Moreover, it has become increasingly evident that lipids play important roles in the autophagy process itself, both at the level of regulation of autophagy and as membrane constituents required for formation of autophagic vesicles (126).…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

Douglas

Lewis

et al. 2016

Journal of Biological Chemistry

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Cytopathic effects are currently believed to contribute to hepatitis C virus (HCV)-induced liver injury and are readily observed in Huh7.5 cells infected with the JFH-1 HCV strain, manifesting as apoptosis highly correlated with growth arrest. Reactive oxygen species, which are induced by HCV infection, have recently emerged as activators of AMP-activated protein kinase. The net effect is ATP conservation via on/off switching of metabolic pathways that produce/consume ATP. Depending on the scenario, this can have either pro-survival or pro-apoptotic effects. We demonstrate reactive oxygen species-mediated activation of AMP-activated kinase in Huh7.5 cells during HCV (JFH-1)-induced growth arrest. Metabolic labeling experiments provided direct evidence that lipid synthesis is attenuated, and ␤-oxidation is enhanced in these cells. A striking increase in nuclear peroxisome proliferator-activated receptor ␣, which plays a dominant role in the expression of ␤-oxidation genes after ligand-induced activation, was also observed, and we provide evidence that peroxisome proliferator-activated receptor ␣ is constitutively activated in these cells. The combination of attenuated lipid synthesis and enhanced ␤-oxidation is not conducive to lipid accumulation, yet cellular lipids still accumulated during this stage of infection. Notably, the serum in the culture media was the only available source for polyunsaturated fatty acids, which were elevated (2-fold) in the infected cells, implicating altered lipid import/export pathways in these cells. This study also provided the first in vivo evidence for enhanced ␤-oxidation during HCV infection because HCV-infected SCID/Alb-uPA mice accumulated higher plasma ketones while fasting than did control mice. Overall, this study highlights the reprogramming of hepatocellular lipid metabolism and bioenergetics during HCV infection, which are predicted to impact both the HCV life cycle and pathogenesis.With ϳ200 million people infected worldwide, hepatitis C virus (HCV) 2 is a global health problem and a major cause of viral hepatitis. Persistent infection occurs in ϳ70% of infected patients leading to inflammation, insulin resistance, steatosis, fibrosis, and hepatocellular carcinoma (1). Current direct-acting antivirals are predicted to be a cure for most patients, but the high cost of this treatment means that the pathological consequences of persistent HCV infection will remain a concern.Although the pathology associated with chronic HCV infection was initially thought to be due to HCV-specific immune responses (2), the current opinion is that direct cytopathic effects in virally infected cells also contribute to HCV-associated liver injury (3, 4). The cellular mechanisms by which HCV replication might mediate liver injury are unclear, but there is no doubt that oxidative/nitrosative stress in HCV-infected cells plays an important role in the initiation and progression of liver damage (3, 5, 6). Oxidative/nitrosative stress essentially arises when the production of reactive oxygen (...

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Autophagy Protects Cells From HCV-Induced Defects in Lipid Metabolism

Cited by 67 publications

References 69 publications

Hepatitis C Virus Upregulates Beclin1 for Induction of Autophagy and Activates mTOR Signaling

Hepatitis C Virus Upregulates Beclin1 for Induction of Autophagy and Activates mTOR Signaling

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

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