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

Calvin Dumesnil, Lauri Vanharanta, Xavier Prasanna, Mohyeddine Omrane, Maxime Carpentier, Apoorva Bhapkar, Giray Enkavi, Veijo T. Salo, Ilpo Vattulainen (), Elina Ikonen () and Abdou Rachid Thiam ()
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Calvin Dumesnil: Sorbonne Université, Université Paris Cité
Lauri Vanharanta: University of Helsinki
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
Ilpo Vattulainen: University of Helsinki
Elina Ikonen: University of Helsinki
Abdou Rachid Thiam: Sorbonne Université, Université Paris Cité

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36375-6

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