title: Plasmodium salvages cholesterol internalized by LDL and synthesized de novo in the liver.
abstract: Our previous morphological studies illustrated the association of sterols with Plasmodium infecting hepatocytes. Because malaria parasites cannot synthesize sterols, they must scavenge these lipids from the host. In this paper, we have examined the source/s of sterols for intrahepatic Plasmodium and evaluated the importance of sterols for liver stage development. We show that Plasmodium continuously diverts cholesterol from hepatocytes until release of merozoites. Removal of plasma lipoproteins from the medium results in a 70% reduction of cholesterol content in hepatic merozoites but these parasites remain infectious in animals. Plasmodium salvages cholesterol that has been internalized by low-density lipoprotein but reduced expression of host low-density lipoprotein receptors by 70% does not influence liver stage burden. Plasmodium is also able to intercept cholesterol synthesized by hepatocytes. Pharmacological blockade of host squalene synthase or downregulation of the expression of this enzyme by 80% decreases by twofold the cholesterol content of merozoites without further impacting parasite development. These data enlighten that, on one hand, malaria parasites have moderate need of sterols for optimal development in hepatocytes and, on the other hand, they can adapt to survive in cholesterol-restrictive conditions by exploitation of accessible sterols derived from alternative sources in hepatocytes to maintain proper infectivity.
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health and Malaria Research Institute, Baltimore, MD 21205, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Labaied
authors.forename: Bamini
authors.initials: B
authors.lastname: Jayabalasingham
authors.forename: Nazneen
authors.initials: N
authors.lastname: Bano
authors.forename: Sung-Jae
authors.initials: SJ
authors.lastname: Cha
authors.forename: Juan
authors.initials: J
authors.lastname: Sandoval
authors.forename: Guimin
authors.initials: G
authors.lastname: Guan
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
mesh_terms: D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D009033:Culicidae / Q000469:parasitology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D052940:Merozoites / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010961:Plasmodium / Q000378:metabolism*; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013261:Sterols / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D013261:Sterols; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase