Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity
| Autor: | Benjamin Schulte, Belén Carriquí-Madroñal, Rina Ötjengerdes, Thomas von Hahn, Gisa Gerold, Benjamin Maasoumy, Julie Sheldon, Francisco J. Zapatero-Belinchón, Florian W. R. Vondran, Laura M. Arroyo-Fernández, Graham Brogden |
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| Přispěvatelé: | TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
hepatitis C virus Very low-density lipoprotein Infektionsmedicin Hepacivirus Pharmacology Virus Replication Cohort Studies SR-B1 0302 clinical medicine LDLr lipid metabolism Medicine Biology (General) PCSK9‑inhibitor Cells Cultured Hypolipidemic Agents Fenofibrate fibrate biology lipoprotein receptor virus diseases Alanine Transaminase General Medicine Hepatitis C Cholesterol HMG-CoA reductase HCV 030211 gastroenterology & hepatology lipids (amino acids peptides and proteins) Mevalonate pathway medicine.drug Infectious Medicine Statin Genotype QH301-705.5 medicine.drug_class Article Cell Line 03 medical and health sciences Humans Aspartate Aminotransferases Glycoproteins Receptors Lipoprotein HMG-CoA-reductase inhibitor business.industry PCSK9-inhibitor statin Lipid metabolism Virus Internalization lipid-lowering drug digestive system diseases 030104 developmental biology LDL receptor biology.protein Hepatocytes Hydroxymethylglutaryl-CoA Reductase Inhibitors business Lipoprotein |
| Zdroj: | Cells Volume 10 Issue 7 Switzerland Cells, Vol 10, Iss 1626, p 1626 (2021) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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