Non-vesicular sterol transport in cells

Abstract

Sterols such as cholesterol are important components of cellular membranes. They are not uniformly distributed among organelles and maintaining the proper distribution of sterols is critical for many cellular functions. Both vesicular and non-vesicular pathways move sterols between membranes and into and out of cells. There is growing evidence that a number of non-vesicular transport pathways operate in cells and, in the past few years, a number of proteins have been proposed to facilitate this transfer. Some are soluble sterol transfer proteins that may move sterol between membranes. Others are integral membranes proteins that mediate sterol efflux, uptake from cells, and perhaps intracellular sterol transfer as well. In most cases, the mechanisms and regulation of these proteins remains poorly understood. This review summarizes our current knowledge of these proteins and how they could contribute to intracellular sterol trafficking and distribution.

Figure 1

Non-vesicular sterol transport pathways in cells. Pathways that are only speculative are marked with a “?”. Non-vesicular sterol transport pathways probably move sterols between the ER and many organelles, perhaps at membrane contact sites. Organelles shown: endoplasmic reticulum (ER), plasma membrane (PM), inner mitochondrial membrane (IMM), outer mitochondrial membrane (OMM), endocytic recycling compartment (ERC), lipid droplet (LD), and external acceptor, which could be a lipoproteins or detergent micelle depending on cell type. Some of the proteins mentioned in the text are shown in blue. It should be noted that all of these proteins are not expressed in the same cells.

Figure 2

Possible mechanisms of non-vesicular sterol transfer. Sterols are shown in red, the membranes bilayer is light blue. A. Spontaneous movement of sterols through the aqueous phase. Sterol in “condensed complexes,” perhaps sterol-sphingolipid enriched microdomains (see text), probably desorbs from membranes more slowly than sterols outside such domains. B. Transfer by soluble lipid transfer proteins (LTPs). These proteins could bind membranes directly when they extract or deliver sterols. Alternatively, they may bind sterols in the aqueous phase. C. Sterol transfer by membrane proteins. These proteins could facilitate transfer between membranes and external acceptors like lipoproteins during sterol uptake or efflux. They could also facilitate sterol movement to LTPs or directly to another membrane. D. Sterols and other lipids could be exchanged between membranes that do not subsequently fuse by transient hemifusion. There is no evidence that this mechanism is used in cells.