A prospective mechanism and source of cholesterol uptake by Plasmodium falciparum-infected erythrocytes co-cultured with HepG2 cells
A prospective mechanism and source of cholesterol uptake by Plasmodium falciparum-infected erythrocytes co-cultured with HepG2 cells
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DOI：
10.1016/j.parint.2020.102179
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发表时间：
2021-02-01
影响因子：
1.9
通讯作者：
Usukura, Jiro
中科院分区：
文献类型：
--
作者：
Hayakawa, Eri H.;Kato, Hirotomo;Usukura, Jiro
恶性疟原虫（P. falciparum）寄生虫仍然在全球范围内引起致命感染，特别是在非洲（https：//www.who.int/publications/i/item/world-malaria-report-2019）。在人类恶性疟原虫血液阶段感染期间，血液中的低密度脂蛋白、高密度脂蛋白和胆固醇水平变低。由于恶性疟原虫缺乏从头胆固醇合成途径，它必须从周围环境中输入胆固醇。然而，胆固醇的起源以及它如何被寄生虫吸收穿过围绕它的多个膜尚不完全清楚。为了回答这个问题，我们使用了胆固醇合成抑制剂（辛伐他汀），胆固醇转运抑制剂（依折麦布），和过氧化物酶体增殖物激活受体α的活化配体，称为环丙贝特，研究这些药物对恶性疟原虫红细胞内生长的影响，无论是否有HepG 2细胞作为脂蛋白饲养细胞。在存在依折麦布的情况下，恶性疟原虫生长受到抑制，但当在共培养系统中使用时，依折麦布在抑制恶性疟原虫生长方面不是非常有效，这与辛伐他汀不同，辛伐他汀在该系统中强烈促进寄生虫生长。已知依折麦布通过阻断尼曼匹克C1样1（NPC 1 L1）蛋白的活性来抑制胆固醇吸收，已知辛伐他汀可增强NPC 1 L1在人体小肠中的表达。总的来说，我们的研究结果支持恶性疟原虫的胆固醇输入涉及肝细胞的可能性，并且在恶性疟原虫生命周期的红细胞期阶段，胆固醇通过NPC 1 L1蛋白或NPC 1 L1同系物摄入寄生虫。
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 alpha, 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 NiemannPick 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.