Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus
| Autor: | Jamie T. Lewis, William R. Addison, Anwar Anwar-Mohamed, Donna N. Douglas, Christopher Hao Pu, Rakesh Bhat, Garry Lund, Michael Logan, Norman M. Kneteman, Richard Lehner |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Carcinoma Hepatocellular Hepacivirus Mice SCID Biology medicine.disease_cause Biochemistry Mice 03 medical and health sciences medicine Animals Humans PPAR alpha Protein kinase A Molecular Biology chemistry.chemical_classification Reactive oxygen species Kinase Fatty Acids Liver Neoplasms Lipid metabolism Cell Biology Peroxisome Hepatitis C Lipids Molecular biology Mitochondria Oxidative Stress 030104 developmental biology Liver chemistry Apoptosis Lipogenesis Oxidation-Reduction Oxidative stress |
| Zdroj: | Journal of Biological Chemistry. 291:1974-1990 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m115.674861 |
| Popis: | 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 β-oxidation is enhanced in these cells. A striking increase in nuclear peroxisome proliferator-activated receptor α, which plays a dominant role in the expression of β-oxidation genes after ligand-induced activation, was also observed, and we provide evidence that peroxisome proliferator-activated receptor α is constitutively activated in these cells. The combination of attenuated lipid synthesis and enhanced β-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 β-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. |
| Databáze: | OpenAIRE |
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