Cholesterol signaling


Cholesterol is a signaling molecule. In human health, its effects are most notable in inflammation and metabolic syndrome. At the molecular level, cholesterol primarily signals by regulating lipid rafts and raft associated membrane protein translocation.

Mechanism

are loosely defined as regions of lipid heterogeneity in cellular membranes.

Raft regulation

Cholesterol regulates the function of a particular type of ordered lipid consisting of long chain saturated acyl chains. A subset can be identified with GM1 sugars and are called GM1 lipid rafts. Cholesterol directly regulates the affinity of palmitoylated proteins for GM1 containing lipid rafts. Cholesterol signaling through lipid rafts attenuated by phosphatidylinositol 4,5 bisphophate signaling. PIP2 contains mostly polyunsaturated lipids that partition away from saturated lipids. Proteins that bind both lipid rafts and PIP2 negatively regulated by high levels of PIP2. This was seen for phopholipiase D.

Substrate presentation

A protein that is regulated by raft associated protein translocation can be activated by substrate presentation. For example if an enzyme translocate in the membrane to its substrate it can be activated by localization to its substrate independent of a conformational change in the enzyme.

Protein ligand

When cholesterol directly binds to a protein and alters its function it can be thought of as a protein ligand.

Ion channels

Cholesterol is thought to bind to cys loop receptors and allosterically modulate their gating.

Role in Disease

Inflammation

During an inflammatory response cholesterol is loaded into immune cells including macrophages. The cholesterol is a signal that activates cytokine production and other inflammatory responses. Cholesterol's role in inflammation is central to many diseases.

Viral entry

Cholesterol loading into cells was recently shown to increase SARS-CoV-2 infectivity.

Coronary Heart Disease

inflammation induced by cholesterol loading into immune cells causes heart disease. A class of drugs called statins blocks cholesterol synthesis and is used extensively in treating heart disease.

Steroids

Cholesterol is precursor for steroid hormones including progestagens, glucocorticoids, mineralocorticoids, androgens, and estrogens.

History

Brown and Goldstein discovered the LDL receptor and showed cholesterol is loaded into cells through receptor mediated endocytosis. Until recently cholesterol was thought of primarily as a structure component of the membrane. However, more recently uptake of cholesterol was shown to signal an immune response in macrophages. More importantly, the ability to efflux cholesterol through ABC transporters is the signal to shut down the inflammatory response.