Nonvesicular cholesterol transport in physiology
Alessandra Ferrari, Peter Tontonoz
Alessandra Ferrari, Peter Tontonoz
Published March 17, 2025
Citation Information: J Clin Invest. 2025;135(6):e188127. https://doi.org/10.1172/JCI188127.
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Review

Nonvesicular cholesterol transport in physiology

Abstract

In mammalian cells cholesterol can be synthesized endogenously or obtained exogenously through lipoprotein uptake. Plasma membrane (PM) is the primary intracellular destination for both sources of cholesterol, and maintaining appropriate membrane cholesterol levels is critical for cellular viability. The endoplasmic reticulum (ER) acts as a cellular cholesterol sensor, regulating synthesis in response to cellular needs and determining the metabolic fates of cholesterol. Upon reaching the ER, cholesterol can be esterified to facilitate its incorporation into lipoproteins and lipid droplets or converted into other molecules such as bile acids and oxysterols. In recent years, it has become clear that the intracellular redistribution of lipids, including cholesterol, is critical for the regulation of various biological processes. This Review highlights physiology and mechanisms of nonvesicular (protein-mediated) intracellular cholesterol trafficking, with a focus on the role of Aster proteins in PM to ER cholesterol transport.

Authors

Alessandra Ferrari, Peter Tontonoz

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Figure 2

Membrane contact sites are involved in nonvesicular cholesterol trafficking.

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Membrane contact sites are involved in nonvesicular cholesterol traffick...
OSBP facilitates the transport of cholesterol from the ER to the trans-Golgi network (TGN) in exchange for phosphatidylinositol 4-phosphate (PI4P). OSBP also mediates cholesterol transport from the ER to the late endosomes/lysosomes (LELs) and from recycling endosomes (REs) to the TGN. ORP1S and ORP2 mediate the transport of cholesterol from LELs to the plasma membrane (PM). ORP1L supports endosomal sorting and forms ER–LEL/multivesicular body tethers, and was proposed to be a mediator of cholesterol trafficking between these organelles. STARD3 transports cholesterol from ER to endosomes. Aster proteins form PM-ER contact sites upon cellular cholesterol loading and move the PM pool of accessible cholesterol to the ER. Mechanisms of nonvesicular cholesterol trafficking to mitochondria through lipid droplet–mitochondria (LD-mitochondria), ER-mitochondria, and endosome-mitochondria contact sites have been postulated. Further studies are needed to elucidate which proteins mediate cholesterol trafficking at these membrane contact sites.