Intracellular sterol dynamics

Abstract

We review the cellular mechanisms implicated in cholesterol trafficking and distribution. Recent studies have provided new information about the distribution of sterols within cells, including analysis of its transbilayer distribution. The cholesterol interaction with other lipids and its engagement in various trafficking processes will determine its proper level in a specific membrane; making the cholesterol distribution uneven among the various intracellular organelles. The cholesterol content is important since cholesterol plays an essential role in membranes by controlling their physicochemical properties as well as key cellular events such as signal transduction and protein trafficking. Cholesterol movement between cellular organelles is highly dynamic, and can be achieved by vesicular and non-vesicular processes. Various studies have analyzed the proteins that play a significant role in these processes, giving us new information about the relative importance of these two trafficking pathways in cholesterol transport. Although still poorly characterized in many trafficking routes, several potential sterol transport proteins have been described in detail; as a result, molecular mechanisms for sterol transport among membranes start to be appreciated.

Figure 1. Structural interactions between cholesterol and other lipids

The sterol stability in a membrane depends on its interaction with neighboring lipids. A. Lipids bearing large polar head groups are preferred partners for cholesterol because they provide better protection from water. B. The level of acyl chain saturation also influences the sterol stability because it is directly related to the lipid shape. Lipids with unsaturated acyl chains containing one double bond are more bulky than lipids with saturated chains; these unsaturated lipids are less suited to afford protection from water to the neighboring cholesterol. C. Poorly protected sterols (e.g., in a DOPC-rich bilayer) have a high chemical activity coefficient; they can leave the membrane readily. In contrast, well protected sterols form with their associated lipids a structure of low chemical activity coefficient. DOPC, dioleoyl-phosphatidylcholine (PC); POPC, palmitoyl-oleoyl-PC; DPPC, dipalmitoyl-PC.

Figure 2. Intracellular cholesterol movements

The circulating LDL particles carrying cholesterol and cholesteryl-ester are internalized through LDL receptor and transported to sorting endosomes (1, 2). LDL particles are subsequently transported to LE and LY (3), while LDL receptors are recycled via the ERC to the PM (4). Cholesteryl-ester hydrolysis by specific lipases such as LAL in LE/LY produces free cholesterol that can efflux from these compartments to other intracellular membranes, such as PM, mostly by non-vesicular transport (5). A precise mechanism for free cholesterol egress from LE/LY is still lacking; however, the membrane-embedded NPC1 and the soluble luminal NPC2 proteins are both required in this process (inset). Cholesterol in the PM can traffic to the ERC by a non-vesicular mechanism; whereas recycling of cholesterol from this compartment back to the PM occurs partly by vesicular and non-vesicular processes (6). Cholesterol translocation from PM to ER allows the homeostatic machinery to be informed about the free cholesterol levels in the cell (7). When it is in excess, the free cholesterol is esterified by ACAT, and fatty acid sterol esters are packed into lipid droplets (8). Newly synthesized cholesterol in the ER is transported mostly to the PM by a non-vesicular process bypassing the Golgi, although some of it would follow the secretory pathway, passing through the Golgi (9).