Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis

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Abstract

When human fibroblasts take up plasma low density lipoprotein (LDL), its cholesterol is liberated in lysosomes and eventually reaches the endoplasmic reticulum (ER) where it inhibits cholesterol synthesis by blocking activation of SREBPs. This feedback protects against cholesterol overaccumulation in the plasma membrane (PM). But how does ER know whether PM is saturated with cholesterol? Here, we define three pools of PM cholesterol: 1) a pool accessible to bind 125I-PFO*, a mutant form of bacterial Perfringolysin O, which binds cholesterol in membranes; 2) a sphingomyelin(SM)-sequestered pool that binds 125I-PFO* only after SM is destroyed by sphingomyelinase; and 3) a residual pool that does not bind 125I-PFO* even after sphingomyelinase treatment. When LDL-derived cholesterol leaves lysosomes, it expands PM's PFO-accessible pool and, after a short lag, it also increases the ER's PFO-accessible regulatory pool. This regulatory mechanism allows cells to ensure optimal cholesterol levels in PM while avoiding cholesterol overaccumulation.

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Akash Das

The University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.
Michael S Brown

The University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
Michael S Brown, Reviewing editor, eLife.
Donald D Anderson

The University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.
Joseph L Goldstein

University of Texas Southwestern Medical Center, Dallas, United States

For correspondence
joe.goldstein@utsouthwestern.edu

Competing interests
No competing interests declared.
Arun Radhakrishnan

The University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.