From measurements of the autocorrelation function and time-averaged intensity of light scattered from aqueous bile salt-lecithin solutions, we deduced the mean hydrodynamic radius (Rh), shape, and polydispersity of bile salt-lecithin mixed micelles as functions of bile salt species, lecithin to bile salt (L/BS) molar ratio, total lipid concentration (0.625-10 g/dL), temperature (20-60 degrees C), and NaCl concentration (0.15-0.6 M). Our data suggest that at low L/BS ratios (0 to approximately 0.6) simple bile salt micelles coexist in varying proportions with minimum-sized mixed micelles (Rh, 18-35 A). These solutions are highly polydisperse and display features dependent upon the particular bile salt species. At high L/BS ratios (greater than 0.6), only mixed micelles are present, and their sizes increase markedly (Rh, 20 leads to 300 A) with increases in L/BS ratio and appear to diverge as the lecithin-bile salt phase limit is approached. The shape of the mixed micelles as deduced from light-scattering measurements and confirmed by transmission electron microscopy is disklike. The radii of the disks, however, are not compatible with Small's model of mixed micellar structure [Small, D.M. (1967a) Gastroenterology 52, 607-a1 but are consistent with a new model proposed here in which bile salts and lecithin interact to form a mixed bilayer disk which is surrounded on its perimeter by bile salts. The inclusion of bile salts in a fixed stoichiometry within the interior of the bilayers is shown to provide a quantitative explanation for the divergence of the mixed micellar sizes, their temperature dependence, and the origin of the lecithin-bile salt phase limit. The influence of total lipid concentration on both mixed micellar size and the lecithin-bile salt phase limit is explained by the "mixed disk" model by taking account of the equilibrium between mixed micelles and bile salt monomers in the intermicellar solution. By use of this concept, deductions of the intermicellar bile salt concentration in taurocholate-lecithin solutions are made and are shown to vary as a function of mixed micellar size and temperature. The range of values obtained, 3-6 mM, is comparable in magnitude to the critical micellar concentration of the pure bile salt.

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Publication costs assisted by the National Science Foundation and National Institutes of Health Measurements of the autocorrelation function and average intensity of light quasielastically scattered from aqueous solutions of sodium dodecyl sulfate (SDS) in the presence of added NaCl were carried out over a wide region of the micellar phase and in the supercooled state below the critical micellar temperature (cmt). The mean size, shape, aggregation number, and polydispersity of SDS micelles have been deduced as a function of température (10-85 °C) and NaCl concentration (0.15-0.6 M) for detergent concentrations (1.7 X IQ-2, 3.5 X 10~2, and 6.9 X 10~2 M) which appreciably exceed the critical micellar concentration (cmc). At these SDS concentrations the size and shape of the micelles show a marked dependence on the temperature and NaCl concentration. A minimum micellar size corresponding to a sphere with a hydrated radius of about 25 Á is asymptotically approached at high temperature in all NaCl concentrations. In NaCl concentrations greater than 0.3 M significant micellar growth occurs as the temperature is.lowered, and the enlarged SDS micelle can be approximated by a prolate ellipsoid with a semiminor axis of 25 Á and a semimajor axis that approaches 675 A in 0.6 M NaCl. The mean aggregation numbers of these rodlike micelles were found to vary approximately with the square root of thé SDS concentration, and the width of the distribution of aggregation numbers was estimated at ±70% of the mean value. In supercooled solutions, micellar size and shape have the same dependence on detergent concentration, NaCl concentration, and temperature as occurs above the crht. It is demonstrated that the cmt, its dependence on NaCl concentration, and the metastability of supercooled micellar solutions can be qualitatively understood by an extension of the Murray-Hartley theory of detergent solubility which accounts for the cmt phenomenon on the basis of the coupling between the monomer-hydrated solid equilibrium and the monomer-micelle equilibrium.

Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1 beta (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.

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Following the feeding of a triacylglycerol-rich meal to healthy adult human beings, duodenal contents were aspirated for ex vivo chemical and physical-chemical analyses. The aspirates were collected during established lipid digestion and absorption into a "cocktail" of chemical inhibitors that rapidly inhibited ex vivo lipolysis. Following ultracentrifugation, the lipids separated into a floating oil layer, several interfacial layers, a "clear" or turbid "subphase", and a precipitated "pellet". By chemical and phase analyses, the floating layer was composed of oil-in-water emulsion particles with cores of triacylglycerol (TG), diacylglycerols (DG), and cholesteryl esters (CE) emulsified with a surface coat of partially ionized fatty acids (FA), monoacylglycerols (MG), diacylphosphatidylcholine (PL), and bile salts (BS). The interfacial layers contained similar emulsion particles dispersed among excess emulsifier which adopted a lamellar liquid-crystalline structure. Precipitated pellets were composed principally of emulsifying lipids, with smaller amounts of crystalline calcium soaps and BS. Relative lipid compositions of all but three subphases fell within a two-phase region of the condensed ternary phase diagram (Staggers et al., 1990, companion paper) where saturated mixed micelles composed of BS, FA "acid-soaps", MG, PL, cholesterol (Ch), and traces of DG (and TG) coexisted with unilamellar liquid-crystalline vesicles composed of the same lipids. Attempts to achieve clean separation of vesicles from micelles by repeat ultracentrifugation failed. Compared with the structure and sizes of lipid particles in equilibrated model systems (Staggers et al., 1990), quasielastic light scattering (QLS) analysis revealed that ex vivo micellar sizes (mean hydrodynamic radii, Rh) were similar (less than or equal to 40 A), whereas unilamellar vesicle sizes (Rh = 200-600 A) were appreciably smaller. Two-component QLS analysis of the subphases showed that much larger proportions of lipids were solubilized by micelles than were dispersed as unilamellar vesicles. When followed as functions of time, vesicles frequently dissolved spontaneously into mixed micelles, indicating that, in the nonequilibrium in vivo conditions, the constituent micellar phase was often unsaturated with lipids. These results are consistent with the hypothesis that, during hydrolysis of emulsified DG and TG by luminal lipases, unilamellar vesicles originate in lamellar liquid crystals that form at emulsion-water interfaces in the upper small intestine. In a BS-replete environment, unilamellar vesicles probably represent the primary dispersed product phase of human fat digestion and facilitate the dissolution of lipolytic products into unsaturated mixed micelles.(ABSTRACT TRUNCATED AT 400 WORDS)

A B S T R A C Tboth the curves and the polynomial equations the "percent cholesterol saturation" of fasting gallbladder and hepatic biles from patients with and without gallstones was calculated and both methods gave similar values. These results demonstrate that by employing cholesterol saturation values appropriate to the total lipid concentration (range 0.2-24.9 g/dl) of individual biles, all cholesterol stone patients have supersaturated gallbladder biles, (mean, 132% [normal weight individuals], and 199% [morbidly obese individuals]). With controls and pigment stone patients the mean values were 95 and 98%, respectively, and in both "50% of biles were supersaturated. Fasting hepatic biles were significantly more supersaturated than gallbladder biles (means 228-273%). Cholesterol monohydrate crystals were found in the majority of gallbladder (83%) and hepatic (58%) biles ofcholesterol gallstone patients but were not observed in pigment stone patients or controls. We conclude that of the several factors in addition to the bile salt:lecithin ratios which can influence the cholesterol saturation of bile the total lipid concentration is the predominant determinant physiologically. Our results demonstrate that (a) metastable supersaturation is frequent in both normal and abnormal biles, (b) cholesterol gallstone patients have supersaturated gallbladder and hepatic biles without exception, and (c) the predominant driving force for cholesterol precipitation appears to be the absolute degree of cholesterol supersaturation.