Cholesterol is a cell signaling molecule that is highly regulated in eukaryotic cell membranes. In human health, its effects are most notable in inflammation, metabolic syndrome, and neurodegeneration. At the molecular level, cholesterol primarily signals by regulating clustering of saturated lipids and proteins that depend on clustering for their regulation.
Mechanism
Lipid rafts are loosely defined as clusters of cholesterol and saturated lipids forming regions of lipid heterogeneity in cellular membranes (e.g., the ganglioside GM1). The association of proteins to lipid rafts is cholesterol dependent and regulates the proteins' function (e.g., substrate presentation).
Lipid raft regulation
Cholesterol regulates the function of several membrane proteins associated with lipid rafts. It does so by controlling the formation or depletion of lipid rafts in the plasma membrane. The lipid rafts house the membrane proteins and forming or depleting the lipid rafts moves the proteins in or out of the raft environment, thereby exposing them to a new environment that can activate or deactivate the proteins. For example, cholesterol directly regulates the affinity of palmitoylated proteins for GM1 containing lipid rafts. Cholesterol signaling through lipid rafts can be attenuated by phosphatidylinositol 4,5 bisphosphate signaling (PIP2). PIP2 contains mostly polyunsaturated lipids that partition away from saturated lipids. Proteins that bind both lipid rafts and PIP2 are negatively regulated by high levels of PIP2. This effect was observed with phospholipase D.
In the brain, astrocytes make the cholesterol and transport it to nerves to control their function.
Substrate presentation
A protein subject to regulation through raft-associated translocation can undergo activation upon substrate presentation. For instance, an enzyme that translocates within the membrane towards its substrate can be activated by localizing to the substrate, irrespective of any conformational changes in the enzyme itself.
Protein ligand
In addition to lipid rafts, cholesterol can also interact with proteins that possess lipid-binding domains, such as certain types of sterol-sensing domains or cholesterol recognition/interaction amino acid consensus (CRAC) motifs. These interactions can affect protein conformation, stability, and function, thereby influencing various cellular processes like signal transduction, membrane trafficking, and enzyme activity. As a signaling lipid, cholesterol may act as a ligand.
Ion channels
Numerous ion channels undergo palmitoylation, a lipid modification process. Moreover, a significant subset of ion channels demonstrate a direct affinity for cholesterol binding. The regulation of ion channels by cholesterol can stem from both direct binding interactions and an indirect influence, facilitated by the localization of palmitoylated residues within lipid rafts. It's important to note that these two mechanisms are not mutually exclusive; they can concurrently contribute to the modulation of ion channel activity and localization.
The spatial arrangement of an ion channel can profoundly impact its activation potential. Proposed mechanisms for this phenomenon encompass alterations in membrane thickness and the concentration of lipid molecules critical for signaling. One instance of this is observed in TREK-1 channels, which transition between lipid rafts and PIP2 domains, where they interact with an activating lipid. Similarly, Kir2.1 channels experience inhibition due to cholesterol while being activated by PIP2. Consequently, a transition from cholesterol-enriched GM1 to PIP2-rich domains is anticipated to trigger channel activation. Conversely, the scenario is opposite for nAChR, which responds positively to cholesterol, eliciting its activation.
Role in Disease
Alzheimer's Disease
In the brain, cholesterol is synthesized in astrocytes and transported to neurons with the cholesterol transport protein apolipoprotein E (apoE). The cholesterol controls the clustering of amyloid precursor protein with gamma secretase in GM1 lipid domains. High cholesterol induces APP hydrolysis and the eventual accumulation of amyloid plaques tau phosphorylation. The ApoE isotype4 is the greatest risk factor for sporadic Alzheimer's and this allele was shown to increase cholesterol in mice.