Cholesterol versus cholesterol sulfate: effects on properties of phospholipid bilayers containing docosahexaenoic acid.

The important omega-3 fatty acid docosahexaenoic acid (DHA) is present at high concentration in some membranes that also contain the unusual sterol cholesterol sulfate (CS). The association between these lipids and their effect on membrane structure is presented here. Differential scanning calorimetry (DSC), MC540 fluorescence, erythritol permeability, pressure/area isotherms on lipid monolayers and molecular modeling are used to compare the effect of CS and cholesterol on model phospholipid membranes. By DSC, CS decreases the main phase transition temperature and broadens the transitions of dipalmitolyphosphatidylcholine (DPPC), 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (18:0,18:1 PC) and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (18:0,22:6 PC) to a much larger extent than does cholesterol. In addition CS produces a three-component transition in 18:0,18:1 PC bilayers that is not seen with cholesterol. In a mixed phospholipid bilayer composed of 18:0,18:1 PC/18:0,22:6 PC (1:1, mol/mol), CS at 2.5 membrane mol% or more induces lateral phase separation while cholesterol does not. CS decreases lipid packing density and increases permeability of 18:0,18:1 PC and 18:0,22:6 PC bilayers to a much larger extent than cholesterol. CS disrupts oleic acid-containing bilayers more than those containing DHA. Molecular modeling confirms that the anionic sulfate moiety on CS renders this sterol more polar than cholesterol with the consequence that CS likely resides higher (extends further into the aqueous environment) in the bilayer. CS can therefore be preferentially accommodated into DHA-enriched bilayers where its tetracyclic ring system may fit into the delta 4 pocket of DHA, a location excluded to cholesterol. It is proposed that CS may in part replace the membrane function of cholesterol in DHA-rich membranes.