Regulation of endoplasmic reticulum cholesterol by plasma membrane cholesterol

Theodore L Steck,Yvonne Lange,Mike Rigney,Jin Ye

doi:10.1016/s0022-2275(20)32101-5

Theodore L Steck, Yvonne Lange + Show 2 more

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https://doi.org/10.1016/s0022-2275(20)32101-5

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Abstract

The abundance of cell cholesterol is governed by multiple regulatory proteins in the endoplasmic reticulum (ER) which, in turn, are under the control of the cholesterol in that organelle. But how does ER cholesterol reflect cell (mostly plasma membrane) cholesterol? We have systematically quantitated this relationship for the first time. We found that ER cholesterol in resting human fibroblasts comprised ∼0.5% of the cell total. The ER pool rose by more than 10-fold in less than 1 h as cell cholesterol was increased by ∼50% from below to above its physiological value. The curve describing the dependence of ER on plasma membrane cholesterol had a J shape. Its vertex was at the ambient level of cell cholesterol and thus could correspond to a threshold. A variety of class 2 amphiphiles (e.g., U18666A) rapidly reduced ER cholesterol but caused only minor alterations in the J-curve. In contrast, brief exposure of cells to the oxysterol, 25-hydroxycholesterol, elevated and linearized the J-curve, increasing ER cholesterol at all values of cell cholesterol. This finding can explain the rapid action of oxysterols on cholesterol homeostasis. Other functions have also been observed to depend acutely on the level of plasma membrane cholesterol near its physiological level, perhaps reflecting a cholesterol-dependent structural or organizational transition in the bilayer. Such a physical transition could serve as a set-point above which excess plasma membrane cholesterol is transported to the ER where it would signal regulatory proteins to down-regulate its further accumulation.—Lange, Y., J. Ye, M. Rigney, and T. L. Steck. Regulation of endoplasmic reticulum cholesterol by plasma membrane cholesterol.

Highlights

The abundance of cell cholesterol is governed by multiple regulatory proteins in the endoplasmic reticulum (ER) which, in turn, are under the control of the cholesterol in that organelle
The size of the ER pool would be defined relative to that in the plasma membrane by the rate constants for cholesterol flux between the two pools. We have tested this model by measuring how the ER cholesterol pool responds to variations in bulk cholesterol; whether this relationship shows a threshold; and how this relationship is affected by agents known to alter cholesterol homeostasis
The extraction of plasma membrane cholesterol caused a reduction of ER cholesterol, as in Fig. 1, while supplementation with HPCD-cholesterol complexes evoked a rise in ER cholesterol (Fig. 2A)

Summary

Introduction

The abundance of cell cholesterol is governed by multiple regulatory proteins in the endoplasmic reticulum (ER) which, in turn, are under the control of the cholesterol in that organelle. Other functions have been observed to depend acutely on the level of plasma membrane cholesterol near its physiological level, perhaps reflecting a cholesterol-dependent structural or organizational transition in the bilayer Such a physical transition could serve as a set-point above which excess plasma membrane cholesterol is transported to the ER where it would signal regulatory proteins to down-regulate its further accumulation.—Lange, Y., J. A brisk throughput of plasma membrane cholesterol might flush out the ER pool and continuously adjust it to the appropriate level In this scheme, incoming cholesterol might be governed by a sensor which allocates to the ER a fraction of plasma membrane cholesterol in excess of a threshold set-point [6, 8]. Our results suggest a simple mechanism by which the plasma membrane could set this threshold and sense its cholesterol

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