Abstract

Cholesterol homeostasis is critical for cell function and human health. Cholesterol is heterogeneously distributed among cellular membranes, with the redistribution of endocytosed dietary cholesterol playing a pivotal role in the regulation of cholesterol homeostasis. While gaps remain in our understanding of intracellular dietary cholesterol transport, a highly complex network of pathways is starting to emerge, often involving inter‐dependent vesicular and non‐vesicular transport mechanisms. The last decade has seen a surge in interest in non‐vesicular transport and inter‐organellar communication at membrane contact sites. By providing platforms for protein interactions, signalling events, lipid exchange and calcium flux, membrane contact sites (MCS) are now appreciated as controlling the fate of large amounts of lipid and play central roles in the regulation and co‐ordination of endocytic trafficking. Here, we review the role of MCS in multiple pathways for cholesterol export from the endocytic pathway and highlight the intriguing interplay between vesicular and non‐vesicular transport mechanisms and relationship with neurodegenerative disease.

Highlights

  • In addition to stabilizing the membrane contact sites (MCS), STARD3 and ORP1L can mediate the transport of newly synthesized cholesterol from the endoplasmic reticulum (ER) to endosomes to support endosome maturation.[18,27]

  • It was more recently shown that the soluble sterol transport protein, STARD4, is responsible for mediating delivery of cholesterol from recycling endosomes to the plasma membrane for onward transport to the ER.[46]

  • Interfering with endosome-Golgi retrograde vesicular transport by depletion of Golgi-associated retrograde protein (GARP) resulted in cholesterol accumulation in the late endosomes (LE)/Lys.[49]. These findings demonstrate a significant contribution to cholesterol efflux from the endocytic pathway by retrograde transport to the Golgi

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Summary

Introduction

In addition to stabilizing the MCS, STARD3 and ORP1L can mediate the transport of newly synthesized cholesterol from the ER to endosomes to support endosome maturation.[18,27] Interestingly, both proteins have been implicated, under certain circumstances, in traffic of LDL-derived cholesterol from LE/Lys to ER (discussed in more detail below), suggesting functionality for ER-endocytic organelle contact sites in bidirectional transport of sterols.

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Conclusion

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