Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

Iqbal, Jawed; McRae, Steven; Banaudha, Krishna; Mai, Thi; Waris, Gulam

doi:10.1074/jbc.m113.492314

Cited by 44 publications

(49 citation statements)

References 63 publications

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“…The presence of HCV in these cells and the corresponding supernatants was determined as described previously (33). The cell-free virus was propagated in Huh7.5 cell culture as described previously (32)(33)(34). The expression of HCV protein in HCV-infected cells was analyzed by Western blotting.…”

Section: Methodsmentioning

confidence: 99%

“…The expression of HCV protein in HCV-infected cells was analyzed by Western blotting. The HCV cell culture supernatant was collected at appropriate time points and used to infect naïve Huh7.5 cells at a multiplicity of infection of 1 for 5-6 h at 37°C and 5% CO 2 (32,33). The viral titer in the cell culture supernatant was expressed as focus forming units per milliliter, which was determined by the average number of HCV-NS5A-positive foci detected at the highest dilutions, as described previously (33).…”

Section: Methodsmentioning

confidence: 99%

“…HCV Cell Culture Infection System-Fifteen micrograms of in vitro transcribed J6/JFH-1 RNA was delivered into Huh-7.5 cells by electroporation as described previously (3,28,32). Cells were passaged every 3-5 days.…”

Section: Methodsmentioning

confidence: 99%

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The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism

McRae

Iqbal

Sarkar-Dutta

et al. 2016

Journal of Biological Chemistry

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Hepatitis C virus (HCV) relies on host lipids and lipid droplets for replication and morphogenesis. The accumulation of lipid droplets in infected hepatocytes manifests as hepatosteatosis, a common pathology observed in chronic hepatitis C patients. One way by which HCV promotes the accumulation of intracellular lipids is through enhancing de novo lipogenesis by activating the sterol regulatory element-binding proteins (SREBPs). In general, activation of SREBPs occurs during cholesterol depletion. Interestingly, during HCV infection, the activation of SREBPs occurs under normal cholesterol levels, but the underlying mechanisms are still elusive. Our previous study has demonstrated the activation of the inflammasome complex in HCVinfected human hepatoma cells. In this study, we elucidate the potential link between chronic hepatitis C-associated inflammation and alteration of lipid homeostasis in infected cells. Our results reveal that the HCV-activated NLRP3 inflammasome is required for the up-regulation of lipogenic genes such as 3-hydroxy-3-methylglutaryl-coenzyme A synthase, fatty acid synthase, and stearoyl-CoA desaturase. Using pharmacological inhibitors and siRNA against the inflammasome components (NLRP3, apoptosis-associated speck-like protein containing a CARD, and caspase-1), we further show that the activation of the NLRP3 inflammasome plays a critical role in lipid droplet formation. NLRP3 inflammasome activation in HCV-infected cells enables caspase-1-mediated degradation of insulin-induced gene proteins. This subsequently leads to the transport of the SREBP cleavage-activating protein⅐SREBP complex from the endoplasmic reticulum to the Golgi, followed by proteolytic activation of SREBPs by S1P and S2P in the Golgi. Typically, inflammasome activation leads to viral clearance. Paradoxically, here we demonstrate how HCV exploits the NLRP3 inflammasome to activate SREBPs and host lipid metabolism, leading to liver disease pathogenesis associated with chronic HCV.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism

McRae

Iqbal

Sarkar-Dutta

et al. 2016

Journal of Biological Chemistry

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“…[55][56][57][58] Reports that Sp1 plays a role in liver injury are more anecdotal. [59][60][61] To confirm the role of these four factors, we performed ChIP-seq on liver samples 1 and 14 days after ligation. Increased Jun binding occurred at both time points.…”

Section: Resultsmentioning

confidence: 99%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

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“…c-Kit promoter activity is known to be upregulated by Sp1 (27). In previous studies, we and others have reported that HCV core enhances Sp1 promoter activity (28,29), which may be a mechanism by which c-Kit expression is enhanced in the presence of HCV.…”

Section: Resultsmentioning

confidence: 99%

Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes

Kwon

Bose

Steele

et al. 2015

J Virol

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We have previously reported that hepatitis C virus (HCV) infection of primary human hepatocytes (PHH IMPORTANCEHCV infection may develop into HCC as an end-stage liver disease. We focused on understanding the mechanism for the risk of HCC from chronic HCV infection and identified targets for treatment. HCV-infected primary and transformed human hepatocytes (PHH or THH) generated CSC. HCV-induced spheres were highly sensitive to cell death from sorafenib and stattic treatment. Thus, our study is highly significant for HCV-associated HCC, with the potential for developing a target-specific strategy for improved therapies.

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Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

Cited by 44 publications

References 63 publications

The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism

The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes

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