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

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

Zapatero-Belinchón, Francisco J. (author): Umeå universitet,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Avdelningen för virologi,Centre for Experimental and Clinical Infection Research, Institute for Experimental Virology, TWINCORE, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Institute of Molecular Biology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Braunschweig, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany

Ötjengerdes, Rina (author): Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Institute of Molecular Biology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig site, Braunschweig, Germany

Sheldon, Julie (author): Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany

Schulte, Benjamin (author): Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig site, Braunschweig, Germany

Carriquí-Madroñal, Belén (author): Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany

Brogden, Graham (author): Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany

Arroyo-Fernández, Laura M. (author): Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany

Vondran, Florian W. R. (author): German Center for Infection Research (DZIF), Hannover-Braunschweig site, Braunschweig, Germany; Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany

Maasoumy, Benjamin (author): Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig site, Braunschweig, Germany

von Hahn, Thomas (author): Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Interventional Endoscopy, Asklepios Hospital Barmbek, Semmelweis University, Campus Hamburg, Hamburg, Germany

Gerold, Gisa, 1979- (author): Umeå universitet,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Avdelningen för virologi,Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany

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2021-06-29
2021
English.
In: Cells. - : MDPI. - 2073-4409. ; 10:7

Related links:: https://doi.org/10.3...; show more...; https://umu.diva-por... (primary) (Raw object); https://www.mdpi.com...; https://urn.kb.se/re...; https://doi.org/10.3...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)

Keyword

fibrate
HCV
hepatitis C virus
HMG-CoA-reductase inhibitor
LDLr
lipid metabolism
lipid-lowering drug
lipoprotein receptor
PCSK9‑inhibitor
SR-B1
statin

Publication and Content Type

ref (subject category)
art (subject category)

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By the author/editor: Zapatero-Belinch ...; Ötjengerdes, Rin ...; Sheldon, Julie; Schulte, Benjami ...; Carriquí-Madroña ...; Brogden, Graham; show more...; Arroyo-Fernández ...; Vondran, Florian ...; Maasoumy, Benjam ...; von Hahn, Thomas; Gerold, Gisa, 19 ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Infectious Medic ...

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By the university: Umeå University

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