Transbilayer organization of membrane cholesterol at low concentrations: Implications in health and disease

Abstract

Cholesterol is an essential and representative lipid in higher eukaryotic cellular membranes and is often found distributed nonrandomly in domains in biological membranes. A large body of literature exists on the organization of cholesterol in plasma membranes or membranes with high cholesterol content. However, very little is known about organization of cholesterol in membranes containing low amounts of cholesterol such as the endoplasmic reticulum or inner mitochondrial membranes. In this review, we have traced the discovery and subsequent development of the concept of transbilayer cholesterol dimers (domains) in membranes at low concentrations. We have further discussed the role of membrane curvature and thickness on the transbilayer organization of cholesterol. Interestingly, this type of cholesterol organization could be relevant in cellular sorting and trafficking, and in pathological conditions.

Cholesterol-induced changes in hippocampal membranes utilizing a phase-sensitive fluorescence probe

“…A number of neurological disorders share a common etiology of defective cholesterol metabolism in the brain [11]. A hallmark of membrane cholesterol is its nonrandom localization in domains in biological and model membranes [12][13][14]. Cholesterol is unique in its ability to form liquid-ordered-like phases in higher eukaryotic plasma membranes [15].…”

Cholesterol through the Looking Glass

“…Cholesterol is known to influence membrane fluidity and thickness (42). In addition, cholesterol may form particular structures in membranes like the hexagonal configuration also observed with phosphatidylethanolamine (20).…”

Cholesterol: An evergreen molecule in biology

“…Evidence for specific organization of cholesterol in membranes at low concentrations was obtained from three independent studies carried out by various groups ( [7,15,16,28]; reviewed in [10] Fig. 2.…”

“…On the other hand, the rough (β) face characterized by the protruding methyl groups can snugly interact with the bumpy topology of a membrane protein. Adapted and modified from [10]. (c) Molecular etiology of SLOS: defective cholesterol biosynthesis pathway leads to accumulation of 7-DHC, an immediate biosynthetic precursor of cholesterol, differing with cholesterol merely in a double bond (highlighted).…”