Host cell lipids control cholesteryl ester synthesis and storage in intracellular Toxoplasma

Yoshifumi Nishikawa, Friederike Quittnat, Timothy T. Stedman, Dennis R. Voelker, Jae Yeon Choi, Matt Zahn, Mei Yang, Marc Pypaert, Keith A. Joiner, Isabelle Coppens

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

The intracellular protozoan Toxoplasma gondii lacks a de novo mechanism for cholesterol synthesis and therefore must scavenge this essential lipid from the host environment. In this study, we demonstrated that T. gondii diverts cholesterol from low-density lipoproteins for cholesteryl ester synthesis and storage in lipid bodies. We identified and characterized two isoforms of acyl-CoA:cholesterol acyltransferase (ACAT)-related enzymes, designated TgACAT1α and TgACAT1β in T. gondii. Both proteins are coexpressed in the parasite, localized to the endoplasmic reticulum and participate in cholesteryl ester synthesis. In contrast to mammalian ACAT, TgACAT1α and TgACAT1β preferentially incorporate palmitate into cholesteryl esters and present a broad sterol substrate affinity. Mammalian ACAT-deficient cells transfected with either TgACAT1α or TgACAT1β are restored in their capability of cholesterol esterification. TgACAT1α produces steryl esters and forms lipid bodies after transformation in a Saccharomyces cerevisiae mutant strain lacking neutral lipids. In addition to their role as ACAT substrates, host fatty acids and low-density lipoproteins directly serve as Toxoplasma ACAT activators by stimulating cholesteryl ester synthesis and lipid droplet biogenesis. Free fatty acids significantly increase TgACAT1α mRNA levels. Selected cholesterol esterification inhibitors impair parasite growth by rapid disruption of plasma membrane. Altogether, these studies indicate that host lipids govern neutral lipid synthesis in Toxoplasma and that interference with mechanisms of host lipid storage is detrimental to parasite survival in mammalian cells.

Original languageEnglish (US)
Pages (from-to)849-867
Number of pages19
JournalCellular Microbiology
Volume7
Issue number6
DOIs
StatePublished - Jun 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Virology

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    Nishikawa, Y., Quittnat, F., Stedman, T. T., Voelker, D. R., Choi, J. Y., Zahn, M., Yang, M., Pypaert, M., Joiner, K. A., & Coppens, I. (2005). Host cell lipids control cholesteryl ester synthesis and storage in intracellular Toxoplasma. Cellular Microbiology, 7(6), 849-867. https://doi.org/10.1111/j.1462-5822.2005.00518.x