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Nuclear-envelope-associated lipid droplets are enriched in cholesteryl esters and increase during inflammatory signaling

ABSTRACT: Cholesteryl esters (CEs) and triacylglycerols (TAGs) are stored in lipid droplets (LDs), but their compartmentalisation is not well understood. Here, we established a hyperspectral stimulated Raman scattering microscopy system to identify and quantitatively assess CEs and TAGs in individual LDs of human cells. We found that nuclear-envelope-associated lipid droplets (NE-LDs) were enriched in cholesteryl esters compared to lipid droplets in the cytoplasm. Correlative light-volume-electron microscopy revealed that NE-LDs projected towards the cytoplasm and associated with type II nuclear envelope (NE) invaginations. The nuclear envelope localization of sterol O-acyltransferase 1 (SOAT1) contributed to NE-LD generation, as trapping of SOAT1 to the NE further increased their number. Upon stimulation by the pro-inflammatory cytokine TNFα, the number of NE-LDs moderately increased. Moreover, TNFα-induced NF-κB nuclear translocation was fine-tuned by SOAT1: increased SOAT1 activity and NE-LDs associated with faster NF-κB translocation, whereas reduced SOAT1 activity and NE-LDs associated with slower NF-κB translocation. Our findings suggest that the NE is enriched in CEs and that cholesterol esterification can modulate nuclear translocation.

SUBMITTER: Ábel Szkalisity

PROVIDER: S-SCDT-10_1038-S44318-025-00423-2 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Cholesteryl esters (CEs) are the water-insoluble transport and storage form of cholesterol. For both transport and storage, phospholipids and proteins embrace the CEs to form an amphipathic monolayer that surrounds the CEs. CEs are transported extracellularly in lipoproteins and are stored intracellularly as cytoplasmic lipid droplets. To clarify the molecular phenomena related to the above structures, we conducted atomistic molecular-dynamics simulations for a spherical, approximately high density lipoprotein sized lipid droplet comprised of palmitoyl-oleoyl-phosphatidylcholine (POPC) and cholesteryl oleate (CO) molecules. An additional simulation was conducted for a lamellar lipid trilayer consisting of the same lipid constituents. The density profiles showed that COs were located in the core of the spherical droplet. In trilayer simulations, CO molecules were also in the core and formed two denser strata. This is remarkable because the intra- and intermolecular behaviors of the COs were similar to previous findings from bulk COs in the fluid phase. In accordance with previous experimental studies, the solubility of COs in the POPC monolayers was found to be low. The orientation distribution of the sterol moiety with respect to the normal of the system was found to be broad, with mainly isotropic or slightly parallel orientations observed deep in the core of the lipid droplet or the trilayer, respectively. In both systems, the orientation of the sterol moiety changed to perpendicular with respect to the normal close to the phopsholipid monolayers. Of interest, within the POPC monolayers, the intramolecular conformation of the COs varied from the previously proposed horseshoe-like conformation to a more extended one. From a metabolic point of view, the observed solubilization of CEs into the phospholipid monolayers, and the conformation of CEs in the phospholipid monolayers are likely to be important regulatory factors of CE transport and hydrolysis.

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Nuclear-envelope-associated lipid droplets are enriched in cholesteryl esters and increase during inflammatory signaling

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