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A prospective mechanism and source of cholesterol uptake by Plasmodium falciparum-infected erythrocytes co-cultured with HepG2 cells.

Authors
  • Hayakawa, Eri H1
  • Kato, Hirotomo2
  • Nardone, Glenn A3
  • Usukura, Jiro4
  • 1 Division of Medical Zoology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: [email protected] , (Japan)
  • 2 Division of Medical Zoology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan. , (Japan)
  • 3 Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-5766, USA.
  • 4 Institute of Material and Systems for Sustainability, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. , (Japan)
Type
Published Article
Journal
Parasitology international
Publication Date
Aug 25, 2020
Volume
80
Pages
102179–102179
Identifiers
DOI: 10.1016/j.parint.2020.102179
PMID: 32853776
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Plasmodium falciparum (P. falciparum) parasites still cause lethal infections worldwide, especially in Africa (https://www.who.int/publications/i/item/world-malaria-report-2019). During P. falciparum blood-stage infections in humans, low-density lipoprotein, high-density lipoprotein and cholesterol levels in the blood become low. Because P. falciparum lacks a de novo cholesterol synthesis pathway, it must import cholesterol from the surrounding environment. However, the origin of the cholesterol and how it is taken up by the parasite across the multiple membranes that surround it is not fully understood. To answer this, we used a cholesterol synthesis inhibiter (simvastatin), a cholesterol transport inhibitor (ezetimibe), and an activating ligand of the peroxisome proliferator-activated receptor α, called ciprofibrate, to investigate the effects of these agents on the intraerythrocytic growth of P. falciparum, both with and without HepG2 cells as the lipoprotein feeders. P. falciparum growth was inhibited in the presence of ezetimibe, but ezetimibe was not very effective at inhibiting P. falciparum growth when used in the co-culture system, unlike simvastatin, which strongly promoted parasite growth in this system. Ezetimibe is known to inhibit cholesterol absorption by blocking the activity of Niemann-Pick C1 like 1 (NPC1L1) protein, and simvastatin is known to enhance NPC1L1 expression in the human body's small intestine. Collectively, our results support the possibility that cholesterol import by P. falciparum involves hepatocytes, and cholesterol uptake into the parasite occurs via NPC1L1 protein or an NPC1L1 homolog during the erythrocytic stages of the P. falciparum lifecycle. Copyright © 2020 Elsevier B.V. All rights reserved.

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