Cholesterol carriers in human bile: are "lamellae" involved?

Cholesterol, a highly insoluble molecule, is transported in bile by specialized lipid aggregates. On the basis of extensive correlations between laboratory-prepared model biles and surgically harvested native biles, it has become generally accepted that biliary cholesterol is solubilized by simple and mixed micelles, single bilayered (unilamellar) vesicles and, under certain conditions, multilamellar vesicles (liposomes or liquid crystals) all composed of bile salts, lecithin and cholesterol in different proportions. Current concepts suggest that in lithogenic biles multilamellar vesicles result from aggregation and fusion of unilamellar vesicles and are a principal source from which cholesterol precipitates to form gallstones. Recent reports now challenge the prevailing paradigm by proposing that the principal cholesterol-carrying particles in human biles are not micelles but are "lamellae" composed of stacked membrane-like bilayers of lipids. In this article, we provide a critical overview of the experiments that led to the established views of biliary cholesterol transport and to the newer lamellae hypothesis. The principal evidence for lamellae stems from negative-stain electron microscopy, an artifactprone technique when used to study lipid-rich fluids such as bile. We show that lamellar structures represent both the electron microscopic analog of multilamellar vesicles in supersaturated biles that presage the nucleation of cholesterol crystals and an electron microscopic artifact of fossilized mixed micelles that are in fact very tiny (2 to 4 nm in radius) by state-of-the-art noninvasive techniques. We argue further that the lamellae nomenclature improperly equates two fundamentally distinct physical-chemical mechanisms for cholesterol solubilization and dispersion in bile on the basis of identically appearing electron microscopic images.