Cholesterol and the journey of extracellular vesicles

Abstract

Eukaryotic cells employ distinct means to release specific signals and material. Research within the last decade has identified different types of membrane-enclosed structures collectively called extracellular vesicles (EVs) as one of them. EVs fall into two categories depending on their subcellular origin. Exosomes are generated within the endosomal system and reach the extracellular space upon fusion of multivesicular bodies. Microvesicles or microparticles are generated by shedding of the plasma membrane. Sterols are essential components of eukaryotic membranes and serve as precursors or cofactors of numerous signaling molecules; their content and subcellular distribution are tightly controlled. The prominent roles of sterols in cells raise the question of whether and how these components impact EVs. In this review, we compile evidence for cholesterol accumulation in EVs and discuss its possible contribution to their biogenesis, release, and uptake. We also consider potential implications of EVs in cellular sterol homeostasis and in cholesterol-related diseases.

Keywords: atherosclerosis; cellular cholesterol; cholesterol/efflux; diseases/dyslipidemias; endosome; macrophages/monocytes; multivesicular bodies; platelets.

Fig. 1.

Contributions of cholesterol to the journey of EVs. Microvesicles are generated by shedding of the PM possibly in domains with elevated cholesterol content. Specific compartments of the endosomal system enriched in cholesterol produce intraluminal vesicles within MVBs. MVBs are actively transported along microtubules to the cell periphery, where their fusion with the PM leads to release of exosomes. EVs are conveyed to target cells by body fluids, where they activate specific signaling pathways or modify the cellular metabolism after selective capture, such as receptor-mediated endocytosis and macropinocytosis for exosomes. Membrane compartments that are enriched in cholesterol and dedicated to the EVs’ journey are highlighted in red. The raft-enriched proteins, such as CD36, are indicated in green. Note that the size of lipids is not to scale in the different membrane compartments.