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Cholesterol esters form supercooled lipid droplets whose nucleation is facilitated by triacylglycerols

Author

Listed:
  • Calvin Dumesnil

    (Sorbonne Université, Université Paris Cité)

  • Lauri Vanharanta

    (University of Helsinki
    Minerva Foundation Institute for Medical Research)

  • Xavier Prasanna

    (University of Helsinki)

  • Mohyeddine Omrane

    (Sorbonne Université, Université Paris Cité)

  • Maxime Carpentier

    (Sorbonne Université, Université Paris Cité)

  • Apoorva Bhapkar

    (Sorbonne Université, Université Paris Cité)

  • Giray Enkavi

    (University of Helsinki)

  • Veijo T. Salo

    (University of Helsinki
    Minerva Foundation Institute for Medical Research
    European Molecular Biology Laboratory (EMBL))

  • Ilpo Vattulainen

    (University of Helsinki)

  • Elina Ikonen

    (University of Helsinki
    Minerva Foundation Institute for Medical Research)

  • Abdou Rachid Thiam

    (Sorbonne Université, Université Paris Cité)

Abstract

Cellular cholesterol can be metabolized to its fatty acid esters, cholesteryl esters (CEs), to be stored in lipid droplets (LDs). With triacylglycerols (TGs), CEs represent the main neutral lipids in LDs. However, while TG melts at ~4 °C, CE melts at ~44 °C, raising the question of how CE-rich LDs form in cells. Here, we show that CE forms supercooled droplets when the CE concentration in LDs is above 20% to TG and, in particular, liquid-crystalline phases when the fraction of CEs is above 90% at 37 °C. In model bilayers, CEs condense and nucleate droplets when the CE/phospholipid ratio reaches over 10-15%. This concentration is reduced by TG pre-clusters in the membrane that thereby facilitate CE nucleation. Accordingly, blocking TG synthesis in cells is sufficient to strongly dampen CE LD nucleation. Finally, CE LDs emerged at seipins, which cluster and nucleate TG LDs in the ER. However, when TG synthesis is inhibited, similar numbers of LDs are generated in the presence and absence of seipin, suggesting that seipin controls CE LD formation via its TG clustering capacity. Our data point to a unique model whereby TG pre-clusters, favorable at seipins, catalyze the nucleation of CE LDs.

Suggested Citation

  • Calvin Dumesnil & Lauri Vanharanta & Xavier Prasanna & Mohyeddine Omrane & Maxime Carpentier & Apoorva Bhapkar & Giray Enkavi & Veijo T. Salo & Ilpo Vattulainen & Elina Ikonen & Abdou Rachid Thiam, 2023. "Cholesterol esters form supercooled lipid droplets whose nucleation is facilitated by triacylglycerols," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36375-6
    DOI: 10.1038/s41467-023-36375-6
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    References listed on IDEAS

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    1. Daichi Kamiyama & Sayaka Sekine & Benjamin Barsi-Rhyne & Jeffrey Hu & Baohui Chen & Luke A. Gilbert & Hiroaki Ishikawa & Manuel D. Leonetti & Wallace F. Marshall & Jonathan S. Weissman & Bo Huang, 2016. "Versatile protein tagging in cells with split fluorescent protein," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    2. Yoel A. Klug & Justin C. Deme & Robin A. Corey & Mike F. Renne & Phillip J. Stansfeld & Susan M. Lea & Pedro Carvalho, 2021. "Mechanism of lipid droplet formation by the yeast Sei1/Ldb16 Seipin complex," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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