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 1

Overview of whole-body cholesterol transport in mice.

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Overview of whole-body cholesterol transport in mice. Diet-derived chole...
Diet-derived cholesterol is absorbed by enterocytes in small intestine and incorporated into chylomicrons and HDL. Liver and intestine synthesize cholesterol de novo. Hepatic cholesterol is packaged into VLDL and HDL. Chylomicrons and VLDL are enriched in triglycerides (TAG), which are delivered to periphery tissues, including adipose and muscle. TAG-depleted chylomicrons, called chylomicron remnants, are delivered back to liver, where they bind LRP1 and LDLR. TAG-depleted VLDLs are called intermediate-density lipoproteins (IDLs). When IDLs are further depleted of TAG, they become LDL. LDL is taken up by LDLR in liver and by scavenger receptors in macrophages. Efflux of cholesterol from macrophages to HDL initiates reverse cholesterol transport (RCT) to the liver for excretion. HDL-cholesterol is taken up by hepatic SR-BI in the liver and is converted to bile acids for elimination. In mice HDL is the most abundant lipoprotein and delivers cholesterol to steroidogenic organs. ApoA1, apolipoprotein A-I; ApoB, apolipoprotein B.