Abstract
Lipid droplets (LDs) are emerging as key factors in cellular physiology, with roles beyond energy storage, including metabolic homeostasis, signalling and development. Together with a growing list of functions, diverse LD populations are being identified in different tissue types as well as within the context of single cells. Here we summarize recent work highlighting LD diversity from three perspectives: their lipid and protein compositional heterogeneity; differences in abundance, size and spatial organization within cells; and the diverse contacts they form with other organelles, all of which contribute to LD function. We also discuss tools and approaches used to visualize LD heterogeneity, the role of LDs in pathophysiology and disease, and open questions in the field.
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Acknowledgements
We thank Y. Malis for assistance with figures and with research for Table 1. We also thank D. Nicastro and L. Gui for assistance with the cryo-electron tomography images used in Fig. 2. The authors are supported by funding from the National Institutes of Health under awards R35GM119768 and DK126887 (W.M.H.) and R35GM133460 (S.C.).
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Glossary
- Birefringence
-
An optical feature of some materials that allows polarized light to have different refractive indices when it passes through the material, revealing a sometimes rainbow-like diffraction pattern to the polarized light. When used in optical imaging of lipid droplets, smectic liquid–crystalline lipid droplets display a distinctive Maltese cross pattern.
- BODIPY
-
Refers to several fluorescent dyes 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene that partition inside lipid droplets and are used for lipid droplet labelling.
- Fluorogen-activated bimolecular complementation
-
A microscopy technique used in studying organelle contacts where non-fluorescent protein segments are fused to proteins of interest localized on different organelles. When these proteins come together the non-fluorescent segments dimerize, forming a docking site for a fluorescent organic dye molecule that then labels the interaction site.
- Glucose exhaustion
-
A metabolic condition characterized by the depletion of available glucose for cells to utilize in metabolism.
- Macrophage foam cells
-
A pathogenic cell type that accumulates in cardiovascular disease when macrophage cells absorb excess LDL particles and accumulate intracellular lipid droplets rich in cholesteryl esters.
- NRZ–SNARE–RAB18
-
A tethering complex mediated by RAB18 at the lipid droplet interacting with the endoplasmic reticulum-localized NAG–RINT1–ZW10 (NRZ) complex and their associated SNAREs.
- Phase separation
-
The process where a mixture demixes into two distinct liquid phases, driven by interactions between molecules.
- Smectic
-
A phase of a liquid crystal where molecules are arranged in layers.
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Henne, W.M., Cohen, S. Heterogeneity, dynamics and organelle interactions of lipid droplets. Nat Rev Mol Cell Biol (2026). https://doi.org/10.1038/s41580-025-00945-x
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DOI: https://doi.org/10.1038/s41580-025-00945-x
