Regulation of membrane enzymes by lipids

Lipid phase transitions and phase diagrams. II. Mictures involving lipids.

Maximum solubility of cholesterol in phosphatidylcholine and phosphatidylethanolamine bilayers.

Because mucin glycoproteins may be important in the pathophysiology of gallstones, we studied the relationship among biliary lipids, gallbladder mucin secretion, and gallstone formation in cholesterol-fed prairie dogs. Organ culture studies of gallbladder explants revealed that the incorporation of [(3)H]glucosamine into tissue and secretory gallbladder glycoproteins was significantly increased at 3, 5, 8, and 14 d of feeding. Peak secretion of labeled mucin occurred at 5 d, when total tissue and secreted glycoprotein production was fivefold greater than control. Gel filtration of the secreted glycoprotein on Sepharose 4B indicated that the majority of radioactivity was present in a macromolecule of > 1 million molecular weight. The increased secretion of gallbladder mucin was organ specific, in that [(3)H]glucosamine incorporation into glycoproteins of stomach and colon was unaffected by cholesterol feeding. Similarly, the incorporation of [(3)H]mannose into gallbladder membrane glycoproteins was not altered by cholesterol feeding. The rate of glycoprotein synthesis and secretion returned to normal upon withdrawal of the cholesterol diet, and ligation of the cystic duct before cholesterol feeding prevented gallbladder mucin hypersecretion. Both results indicate that the stimulus to mucin secretion was a constituent of bile. Gallbladder bile after 5 d contained cholesterol in micelles, liquid crystals, and crystals, whereas hepatic bile remained a single micellar phase throughout cholesterol feeding. For this reason the cholesterol-saturation indices of gallbladder bile were compared in both homogenized and centrifuged samples. The micellar phase of gallbladder bile was appreciably less saturated than homogenized bile at 5 and 8 d, which reflects the continuous nucleation of cholesterol in the gallbladder. Purified human gallbladder mucin gels were shown to induce nucleation of lecithin-cholesterol liquid crystals from supersaturated hepatic bile. These in turn gave rise to cholesterol monohydrate crystals within 18 h. Control supersaturated hepatic bile could not be nucleated by the addition of other proteins, and was stable for days upon standing. These results suggest that the increase in cholesterol content of bile in cholesterolfed prairie dogs stimulates gallbladder mucus hypersecretion, and that gallbladder mucus gel is a nucleating agent for biliary cholesterol.

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Role of gallbladder mucus hypersecretion in the evolution of cholesterol gallstones.

95 individual human atherosclerotic lesions from 26 persons were classified into three groups under the dissecting microscope: fatty streaks, fibrous plaques, and gruel (atheromatous) plaques. Each lesion was isolated by microdissection, its lipid composition determined by chromatography, and the physical states of the lipids identified by polarizing microscopy and in some cases by X-ray diffraction. The composition of each lesion was plotted on the in vitro phase diagram of the major lipids of plaques: cholesterol, cholesterol ester, and phospholipid. The observed physical states were compared with those predicted by the location of the lipid composition on the phase diagram. The most severe lesions (gruel plaques) had an average lipid composition of cholesterol 31.5+/-1.9%, cholesterol ester 47.2+/-2.3%, and phospholipid 15.3+/-0.5%. Their compositions fell within the three-phase zone of the phase diagram, predicting the lipids to be separated into a cholesterol crystal phase, a cholesterol ester oily phase and a phospholipid liquid crystalline phase. In addition to the phospholipid liquid crystalline phase of membranes and myelin-like figures demonstrable by electron microscopy, polarizing microscopy revealed the other two predicted phases, isotropic cholesterol ester-rich droplets and cholesterol crystals. X-ray diffraction studies verified the identity of the crystals as cholesterol monohydrate. Fibrous plaques also had an average lipid composition within the three-phase zone of the phase diagram. Polarizing microscopy revealed the presence of cholesterol monohydrate crystals and lipid droplets in all of these lesions; the droplets were predominately isotropic in 28 of the 31 fibrous plaques. Although these lesions had less free cholesterol and more cholesterol ester than gruel plaques, they were otherwise similar. Fatty streaks had compositions within both the two- and three-phase zones of the phase diagram. Compared with gruel plaques, the fatty streaks within the two-phase zone, defined as "ordinary," had more cholesterol ester, less free cholesterol, a higher cholesteryl oleate/cholesteryl linoleate ratio, a lower sphingomyelin/lecithin ratio, more anisotropic lipid droplets, and rare or no cholesterol crystals. Those lesions within the three-phase zone had many chemical and physical features intermediate between ordinary fatty streaks and gruel plaques. Moreover, 68% of these "intermediate" lesions had no cholesterol crystals by polarizing microscopy in spite of their compositions being within the three-phase zone, indicating the cholesterol ester oily phase or the phospholipid phase or both were supersaturated with cholesterol. Identification of this group of intermediate lesions provides evidence that some fatty streaks may be precursors of advanced plaques.

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Physical chemistry of the lipids of human atherosclerotic lesions. Demonstration of a lesion intermediate between fatty streaks and advanced plaques.

The phase behavior of hydrated cholesterol.

The ternary phase diagram of lecithin, cholesteryl linolenate and water: Phase behavior and structure

The binary phase diagram of lecithin and cholesteryl linolenate

Lipids are biologically important molecules. They give structure to plasma membranes and intracellular organelles, provide a source of metabolic energy and play a role in many essential biological processes such as transmission of information across membranes, transmission of nerve impulses, antigen-antibody reactions and thrombogenesis. Lipids have also been implicated in pathological processes, for instance the lipid storage diseases (1) gallstones and (2) atherosclerosis (3).

Liquid Crystalline Behavior of Biologically Important Lipids Polyunsaturated Cholesterol Esters and Phospholipids

Among the many organic compounds which form liquid crystalline states, phospholipids and cholesteryl esters are naturally occurring, biologically important molecules. Phospholipids are the major lipid components of cell membranes (1) and together with cholesteryl esters comprise the bulk of lipids found in the circulating lipoproteins of the serum (2). The liquid crystalline nature of these lipids has been shown to be intrinsically important in the structure of both membranes and low density serum lipoproteins (3–5). Certain diseases, in particular atherosclerosis, are associated with the accumulation of phospholipid and cholesteryl ester (6,7). In atherosclerosis, these lipids have been shown to be primarily in their liquid crystalline states at physiological temperature (8).

Carson R. Loomis

Papers

The phase behavior of hydrated cholesterol.

The ternary phase diagram of lecithin, cholesteryl linolenate and water: Phase behavior and structure

The binary phase diagram of lecithin and cholesteryl linolenate

Liquid Crystalline Behavior of Biologically Important Lipids Polyunsaturated Cholesterol Esters and Phospholipids

Liquid Crystalline Interactions Between Cholesteryl Esters and Phospholipids