The effect of sterol structure on membrane lipid domains reveals how cholesterol can induce lipid domain formation

Detergent-insoluble membrane domains, enriched in saturated lipids and chol esterol, have been implicated in numerous biological functions. To understa nd how cholesterol promotes domain formation, the effect of various sterols and sterol derivatives on domain formation in mixtures of the saturated li pid dipalmitoylphosphatidylcholine (DPPC) and a fluorescence quenching anal ogue of an unsaturated lipid was compared. Quenching measurements demonstra ted that several sterols (cholesterol, dihydrocholesterol, epicholesterol, and 25-hydroxycholesterol) promote formation of DPPC-enriched domains. Othe r sterols and sterol derivatives had little effect on domain formation (cho lestane and lanosterol) or, surprisingly, strongly inhibit it (coprostanol, androstenol, cholesterol sulfate, and 4-cholestenone). The effect of stero ls on domain formation was closely correlated with their effects on DPPC in solubility. Those sterols that promoted domain formation increased DPPC ins olubility, whereas those sterols that inhibit domain formation decreased DP PC insolubility. The effects of sterols on the fluorescence polarization of diphenylhexatriene incorporated into DPPC-containing vesicles were also co rrelated with sterol structure. These experiments indicate that the effect of sterol on the ability of saturated lipids to form a tightly packed (i.e. , tight in the sense that the lipids are closely packed with one another) a nd ordered state is the key to their effect on domain formation. Those ster ols that promote tight packing of saturated lipids promote domain formation , while those sterols that inhibited tight packing of saturated lipids inhi bited domain formation. The ability of some sterols to inhibit domain forma tion (i.e., act as "anti-cholesterols'') should be a valuable tool for exam ining domain formation and properties in cells.