Side-chain oxysterols: from cells to membranes to molecules

Abstract

This review discusses the application of cellular biology, molecular biophysics, and computational simulation to understand membrane-mediated mechanisms by which oxysterols regulate cholesterol homeostasis. Side-chain oxysterols, which are produced enzymatically in vivo, are physiological regulators of cholesterol homeostasis and primarily serve as cellular signals for excess cholesterol. These oxysterols regulate cholesterol homeostasis through both transcriptional and non-transcriptional pathways; however, many molecular details of their interactions in these pathways are still not well understood. Cholesterol trafficking provides one mechanism for regulation. The current model of cholesterol trafficking regulation is based on the existence of two distinct cholesterol pools in the membrane: a low and a high availability/activity pool. It is proposed that the low availability/activity pool of cholesterol is integrated into tightly packing phospholipids and relatively inaccessible to water or cellular proteins, while the high availability cholesterol pool is more mobile in the membrane and is present in membranes where the phospholipids are not as compressed. Recent results suggest that oxysterols may promote cholesterol egress from membranes by shifting cholesterol from the low to the high activity pools. Furthermore, molecular simulations suggest a potential mechanism for oxysterol "activation" of cholesterol through its displacement in the membrane. This review discusses these results as well as several other important interactions between oxysterols and cholesterol in cellular and model lipid membranes. This article is part of a Special Issue entitled: Membrane protein structure and function.

Figure 1

An overview of common biological oxysterols, both those produced from attack on cholesterol by reactive oxygen species (7-keto-, 7α-hydroxy-, and 7β-hydroxycholesterol) and those produced enzymatically by the cell (25(S)-hydroxy-, 25-hydroxy-, and 27-hydroxycholesterol).

Figure 2

Pathways of cholesterol homeostasis.

Figure 3

Differences in the preferred orientations of cholesterol (yellow) and 25-HC (green) can clearly be seen, with cholesterol preferring upright and 25-HC tilted orientations. The increased exposure of sterols in the mixed bilayer can be seen as sterols shift into the phospholipid headgroup (blue and ochre) region.