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Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity

The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very-low-density lipoprotein (VLDL) s...

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Autores principales: Zapatero-Belinchón, Francisco J., Ötjengerdes, Rina, Sheldon, Julie, Schulte, Benjamin, Carriquí-Madroñal, Belén, Brogden, Graham, Arroyo-Fernández, Laura M., Vondran, Florian W. R., Maasoumy, Benjamin, von Hahn, Thomas, Gerold, Gisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303410/
https://www.ncbi.nlm.nih.gov/pubmed/34209751
http://dx.doi.org/10.3390/cells10071626
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author Zapatero-Belinchón, Francisco J.
Ötjengerdes, Rina
Sheldon, Julie
Schulte, Benjamin
Carriquí-Madroñal, Belén
Brogden, Graham
Arroyo-Fernández, Laura M.
Vondran, Florian W. R.
Maasoumy, Benjamin
von Hahn, Thomas
Gerold, Gisa
author_facet Zapatero-Belinchón, Francisco J.
Ötjengerdes, Rina
Sheldon, Julie
Schulte, Benjamin
Carriquí-Madroñal, Belén
Brogden, Graham
Arroyo-Fernández, Laura M.
Vondran, Florian W. R.
Maasoumy, Benjamin
von Hahn, Thomas
Gerold, Gisa
author_sort Zapatero-Belinchón, Francisco J.
collection PubMed
description The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very-low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR-B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid-lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle.
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spelling pubmed-83034102021-07-25 Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity Zapatero-Belinchón, Francisco J. Ötjengerdes, Rina Sheldon, Julie Schulte, Benjamin Carriquí-Madroñal, Belén Brogden, Graham Arroyo-Fernández, Laura M. Vondran, Florian W. R. Maasoumy, Benjamin von Hahn, Thomas Gerold, Gisa Cells Article The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very-low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR-B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid-lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle. MDPI 2021-06-29 /pmc/articles/PMC8303410/ /pubmed/34209751 http://dx.doi.org/10.3390/cells10071626 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zapatero-Belinchón, Francisco J.
Ötjengerdes, Rina
Sheldon, Julie
Schulte, Benjamin
Carriquí-Madroñal, Belén
Brogden, Graham
Arroyo-Fernández, Laura M.
Vondran, Florian W. R.
Maasoumy, Benjamin
von Hahn, Thomas
Gerold, Gisa
Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity
title Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity
title_full Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity
title_fullStr Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity
title_full_unstemmed Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity
title_short Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity
title_sort interdependent impact of lipoprotein receptors and lipid-lowering drugs on hcv infectivity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303410/
https://www.ncbi.nlm.nih.gov/pubmed/34209751
http://dx.doi.org/10.3390/cells10071626
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