| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Modification of the effects of estrogen therapy on HDL cholesterol levels by polymorphisms of the HDL-C receptor, SR-BI: the Rancho Bernardo Study Richard, E., D. von Muhlen, et al. (2005), Atherosclerosis 180(2): 255-62. Abstract: BACKGROUND: Previous studies have found polymorphisms of the HDL receptor, SR-BI, to be associated with plasma HDL-C in women, but not men, suggesting a modifying role of estrogen. We examined whether the association between SR-BI genotypes and HDL-C is modified by use of unopposed estrogen in community-dwelling postmenopausal Caucasian women. METHODS: Common polymorphisms in Intron5 and Exon8 of the SR-BI gene were evaluated in 689 women from the Rancho Bernardo Study. Multiple linear regression analysis was carried out adjusting for confounders. RESULTS: HDL-C levels did not differ significantly by genotype in the aggregate population. However, significant interaction was found between estrogen use and Exon8 (p=0.03), Intron5 (p=0.03) and Intron5/Exon8 diplotypes (p=0.01). SR-BI genotype was associated with HDL-C levels only among estrogen users (p=0.05) and explained 5.3% of the variance in HDL-C in this group. Consistent with prior studies, individuals heterozygous at both Intron5 and Exon8 loci had the lowest HDL-C levels. Among women with symptomatic CHD, the interaction between estrogen use and SR-BI genotype became even stronger. CONCLUSIONS: The effect that unopposed estrogen use has on HDL-C may depend on a woman's SR-BI genotype. |
| Modifications in the head group and in the spacer of cholesterol-based cationic lipids promote transfection in melanoma B16-F10 cells and tumours Reynier, P., D. Briane, et al. (2004), J Drug Target 12(1): 25-38. Abstract: A series of four cationic lipids derived from cholesterol was synthesised and their efficiencies to vectorise nucleic acids were compared. The investigation concerns the effects of systematic chemical modifications in the polar head and in the spacer. The cationic lipid molecules used are in the same family of 3betaN-(N',N',N'-trimethylaminoethane)-carbamoyl cholesterol iodide (TMAEC-Chol), presenting a spacer of two or three carbons and a quaternary ammonium polar head ramified with methyl or ethyl groups. These lipids formed stable liposomes sizing from 100 to 200 nm when prepared with the colipid dioleoyl phosphatidylethanolamine (DOPE). The goal of this work was to investigate the effect of the chemical structure of these cationic lipids on lipofection. Their ability to form complexes with DNA, their cytotoxicity and their transfection efficiency in vitro and in vivo were studied. Results were compared with those obtained from the well known cholesterol-based cationic lipid DC-Chol. In a melanoma cell line (B16-F10), results showed that either the polar head or the spacer affected the cytotoxicity. Cationic lipids with three ethyl groups in the head are more toxic than those with three methyl groups while cationic lipids with three carbons in the spacer are less toxic than those with two carbons in the spacer. The best transfection level was obtained in vitro and in vivo with cationic lipids having 3C in the spacer. Data indicated that among these lipids, in vivo gene transfer is advantaged by the methylated polar head while in vitro the best level was obtained with the ethylated one. Finally, it was observed that the chemical structure influences the transfection in the presence of serum while the complex charge and the DOPE ratios in liposomes preferentially affect the interaction with erythrocytes. Argumentations are proposed to explain the discrepancies between in vitro and in vivo transfection results concerning the optimal charge ratio and the chemical nature of the cationic lipid head group. |
| Modifications of vimentin filament architecture and vimentin-nuclear interactions by cholesterol oxides in 73/73 endothelial cells Palladini, G., G. Finardi, et al. (1996), Exp Cell Res 223(1): 83-90. Abstract: Among the different targets of the cytodamaging effects of cholesterol oxides in endothelial cells, cytoskeleton is one of the most relevant, due to the large variety of biological events controlled by this subcellular structure. The modifications of the intermediate filament network caused by three cholesterol oxides (cholestane-3beta,5alpha,6beta-triol, CH, 7-keto-cholesterol, KC, and 25-OH-cholesterol, COH) was investigated in the endothelial cell line 73/73 using immunofluorescence and laser scanner confocal microscopy. All three cholesterol oxides promoted a redistribution of vimentin filaments that took place well before cell detachment and the occurrence of any detectable sign of cell death. CH-induced alterations were characterized by the polarization of vimentin to the edges of the cell and a concomitant destruction of its interaction with the nucleus. In KC-treated cells, vimentin filaments appeared cross-linked and formed a sort of circular network ring between the nucleus and the cell periphery. COH promoted the aggregation of vimentin filaments in thick and irregular bundles that delimited apparently empty regions. All these changes occurred independently of gross modifications in microtubule organization, which was generally retained except for the appearance of immunoreactive tubulin spots throughout the cytoplasm. These results indicate that the organization of the intermediate-size filament protein vimentin is markedly affected by cholesterol oxides. The different rearrangements caused by CH, KC, and COH may derive from different pathobiochemical processes triggered by these compounds. |
| Modified eggs are compatible with a diet that reduces serum cholesterol concentrations in humans Garwin, J. L., J. M. Morgan, et al. (1992), J Nutr 122(11): 2153-60. Abstract: The National Cholesterol Education Program (NCEP) guidelines recommend dietary restriction of fat and cholesterol to reduce high circulating cholesterol concentrations in adult Americans. Thus, diet counselors recommend consumption of fewer than four egg yolks per week. The present protocol was designed to determine whether the efficacy of an NCEP diet would be reduced by the incorporation of 12 modified eggs per week, and whether the resulting low fat, high cholesterol diet would increase serum lipid concentrations in adults with initial undesirably high (5.17-7.76 mmol/L) concentrations of serum total cholesterol. Feeding a controlled ration to laying hens produced modified eggs that consistently contained more vitamin E and iodine, and more unsaturated fat, than generic eggs. Subjects were randomly assigned to and NCEP diet including either no whole eggs or 12 whole study eggs a week. Ninety-eight subjects completed the parallel study. Subjects in both groups significantly reduced their serum total, LDL and HDL cholesterol (P < 0.001 for total and LDL cholesterol, P < 0.02 for HDL cholesterol) over the 6 wk of study. No significant differences were found between diet groups. We conclude that the study eggs did not adversely affect measured lipid concentrations when added to a low fat diet that favorably alters lipid profiles in hypercholesterolemic subjects. |
| Modified linear polyethylenimine-cholesterol conjugates for DNA complexation Furgeson, D. Y., W. S. Chan, et al. (2003), Bioconjug Chem 14(4): 840-7. Abstract: Linear polyethylenimine (LPEI) is an effective nonviral gene carrier with transfection levels equal or above branched polyethylenimine (BPEI) and exhibits a lower cytotoxicity profile than BPEI. High molecular weight LPEI M(w) 25 k was modified with cholesterol in three different geometries: linear shaped (L), T-shaped (T), and a combined linear/T-shaped (LT) forming the LPEI-cholesterol (LPC) conjugates LPC-L, LPC-T, and LPC-LT, respectively. Physical characterization of LPC/pDNA complexes included particle size, zeta potential, DNase protection, mIL-12 p70 expression, and cytotoxicity. The particle size was further confirmed by atomic force microscopy (AFM). The LPC-T/pDNA complexes were optimal at N/P 10/1 that resulted in a particle size of approximately 250 nm, which was confirmed by AFM, and a surface charge of +10 mV. These complexes also effectively protected the pDNA for up to 180 min in the presence of DNase I. B16-F0 cells transfected with LPC-L and LPC-T showed protein expression levels higher than LPEI alone and twice that of BPEI but without any significant loss in cell viability. These results were confirmed with EGFP flow cytometry and transfection of Renca cells. The differences in rates of transfection of the LPC/pDNA complexes is due in part to conformational changes from the point of complex formation to interaction with the plasma membrane. These conformation changes provide protection for unprotonated secondary amines in the LPEI backbone by hydrophobic protection of the cholesterol moiety that we termed "unprotonated reserves". Finally, we show that LPC conjugates exploit receptor-mediated endocytosis via the LDL-R pathway with transgene expression levels decreasing nearly 20% after saturating the LDL-R sites on MCF-7 cells with hLDL-R-Ab. |
| Modified low density lipoprotein from diabetic patients causes cholesterol accumulation in human intimal aortic cells Sobenin, I. A., V. V. Tertov, et al. (1993), Atherosclerosis 100(1): 41-54. Abstract: Fifty-five serum samples from 99 Type 1 and 71 serum samples from 81 Type 2 diabetic patients (56% and 88%, respectively) brought about a 1.5-3.5-fold increase in total cholesterol content of cultured human intimal aortic cells. This atherogenic effect did not correlate with patient's age, diabetes duration or plasma lipid levels, and was mainly due to low density lipoprotein (LDL). Cholesterol accumulation in cells incubated with LDL highly correlated with that in cells exposed to corresponding patient's serum (r = 0.872 and r = 0.811, P < 0.0001, in Type 1 and Type 2 diabetic patients, respectively). In LDL from diabetic patients the sialic acid content was decreased by an average of 30% (P < 0.05), as compared with healthy subjects, and the fructosyl lysine content was increased by an average of 25% (P < 0.05). Atherogenic effect of patients' LDL significantly correlated with their fructosyl lysine content (P < 0.0001) and negatively correlated with sialic acid content (P < 0.0001). Two LDL fractions were further separated from the total LDL preparation by affinity chromatography on Ricinus communis agglutinin-agarose. The bound (desialylated) LDL fraction was characterized by an increased fructosyl lysine content and the altered neutral lipid and phospholipid composition, while non-bound (sialylated) LDL fraction did not differ from normal LDL. Desialylated, but not sialylated, LDL fraction induced massive cholesterol accumulation in cultured cells. In conclusion, the cholesterol accumulating effect of diabetic patients' blood sera is mainly related to atherogenic low density lipoprotein fraction, which is modified in various ways--by increased non-enzymatic glycosylation, desialylation and alterations in lipid composition. This multiple-modified LDL may contribute to the premature atherosclerosis development in diabetes mellitus. |
| Modified method of determination of alpha lipoprotein cholesterol Gutkina, O. N. and G. N. Siniugina (1996), Klin Lab Diagn(3): 52. |
| Modifying dietary fat intake can reduce serum cholesterol in HIV-associated hypercholesterolemia Batterham, M. J., D. Brown, et al. (2003), Aids 17(9): 1414-6. |
| Modifying increased plasma cholesterol levels in secondary prevention of coronary heart disease Jost, S. and P. R. Lichtlen (1995), Z Kardiol 84(8): 577-95. Abstract: In secondary prevention of coronary heart disease, the reduction of elevated cholesterol plasma levels is mainly based on diet and/or drugs. Invasive means such as partial ileal bypass operation or LDL-apheresis, although highly effective in reducing cholesterol levels and incidence of clinical cardiac events, should be reserved for special subgroups of patients. With dietary measures such as strict reduction of calories originating from fat, as well as with increased consumption of fish, fruits, vegetables and cereals, clinical or angiographic benefits could be demonstrated; in addition to the reduction of cholesterol plasma levels, other mechanisms such as inhibition of platelet aggregation and protection of LDL-particles from oxidation may contribute to this effect. With drugs reduction of cardiac events and of cardiac and total mortality was not observed in all clinical studies. Most angiographic drug studies revealed a significant, although quantitatively moderate retardation of the progression of coronary artery disease. However, only in a few studies did the clinical or angiographic effects correlate with the extent of changes in total, LDL- or HDL-cholesterol plasma levels or their absolute values on trial. Women and men seem to benefit equally from drug therapy. The efficiency of cholesterol-lowering measures in patients with age > 70 years is still unknown, however. In patients with coronary artery disease and normal cholesterol plasma levels neither clinical nor angiographic benefits could so far be demonstrated with cholesterol-lowering measures. Thus, to date in the secondary prevention of coronary artery disease cholesterol-lowering therapy with drugs only seems definitely indicated in patients < 70 years of age with hypercholesterolemia resistant to diet. |
| Modifying the fatty acid profile of dairy products through feedlot technology lowers plasma cholesterol of humans consuming the products Noakes, M., P. J. Nestel, et al. (1996), Am J Clin Nutr 63(1): 42-6. Abstract: Intake of milk and butter has been clearly associated with higher coronary heart disease rates in different countries and this is likely to be mediated by the hypercholesterolemic effect of dairy fat. Fat-modified dairy products are an innovation involving a technology in which protected unsaturated lipids are fed to ruminants resulting in milk and tissue lipids with reduced saturated fatty acids. We examined the impact of these novel dairy fats on plasma lipids in a human dietary trial. Thirty-three men and women participated in an 8-wk randomized crossover trial comparing fat-modified with conventional dairy products. The trial consisted of a 2-wk low-fat baseline period followed by two 3-wk intervention phases. During the test periods, the fat-modified products resulted in a significant 0.28-mmol/L (4.3%) lowering of total cholesterol (P < 0.001). Most of this decrease was in LDL cholesterol, which decreased by 0.24 mmol/L (P < 0.001) whereas HDL cholesterol and triacylglycerols remained essentially unchanged. This alteration in the fatty acid profile of dairy products, if applied to populations typical of developed Western countries, represents a potential strategy to lower the risk of coronary heart disease without any appreciable change in customary eating patterns. |
| Modulation by cellular cholesterol of gene transcription via the cyclic AMP response element Middleton, A., D. Nury, et al. (2001), Biochem Pharmacol 62(2): 171-81. Abstract: The effect of rapid changes in cellular cholesterol content on adenosine 3',5'-cyclic monophosphate (cAMP) response element-mediated gene transcription was investigated. The study was carried out in Chinese hamster ovary (CHO-K1) cells permanently expressing the human beta(2)-adrenoceptor. Gene transcription was quantified using a reporter gene (secreted placental alkaline phosphatase) under the transcriptional control of cAMP response element (CRE) sequences. Cellular cholesterol was reduced by 42% or elevated by 47% by incubating cells for 1 hr with methyl-beta-cyclodextrin alone or methyl-beta-cyclodextrin complexed with cholesterol, respectively. There was a significant negative correlation between the free cholesterol content of the cells and CRE-mediated gene expression in response to 10(-6) M isoprenaline (slope = -4.57 +/- 0.73, P < 0.001), indicating that beta(2)-adrenoceptor-mediated activation of the CRE is inhibited by cholesterol. Cyclic AMP accumulation in response to isoprenaline (10(-12) to 10(-5) M) was also inhibited in cholesterol-enriched cells and enhanced in cholesterol-depleted cells compared to controls (P < 0.05, two-way ANOVA). Cholesterol also inhibited serum-mediated enhancement of CRE-driven gene expression, and we present data suggesting that the pathway activated by serum and inhibited by cholesterol could be independent of adrenoceptor activation and protein kinase A. We conclude that in CHO-K1 cells cholesterol inhibits at least two processes that can stimulate CRE-mediated gene expression. One is isoprenaline activation of cAMP synthesis, the other is activated by serum. These findings demonstrate that activation of gene transcription by extracellular stimuli could be influenced by cellular cholesterol content. |
| Modulation of alpha5beta1 integrin functions by the phospholipid and cholesterol contents of cell membranes Gopalakrishna, P., S. K. Chaubey, et al. (2000), J Cell Biochem 77(4): 517-28. Abstract: Several modifications of the alpha5beta1 integrin, which alter its intracellular and extracellular interaction with fibronectin and other proteins, have been reported. However, the significance of the lateral mobility of integrin molecules in the plasma membrane, as a regulator of their distribution and function, is poorly understood. We examined this problem by increasing the cholesterol content of plasma membranes, and consequently modifying the fluidity of membrane phospholipids, in rat fibroblasts. Under these conditions, the clustering of alpha5beta1 integrin molecules in focal adhesions, their adhesion to the cell-binding domain of fibronectin, and their association with the cytoskeletal protein talin were significantly enhanced as compared to control cells. However, the activation of MAP-kinase pathways by the association of fibronectin with alpha5beta1 integrin, and its association with integrin-linked kinase (ilk), were suppressed. The treated cells also showed distinct changes in shape, and their actin stress fiber network was more dense and thick as compared to control cells. The changes in fluidity of phospholipids occurred differentially and fluidity of phosphatidyl-ethanolamine increased, while that of phosphatidyl-choline was reduced. Our results suggest that proteins in focal adhesions could be partitioned in specific lipid domains, which regulate specific aspects of alpha5beta1 integrin functions. |
| Modulation of arterial smooth muscle cells in culture and cholesterol exchange Bourdillon, M. C., E. Dusserre, et al. (1991), Ann Endocrinol (Paris) 52(6): 464-6. Abstract: The phenotypic modulation and the enhanced proliferation of smooth muscle cells (SMC) as well as their foam transformation are major processes in arterial pathophysiology and during atherogenesis. Arterial SMC play a crucial role, in response to several stimuli: the SMC "activation" is an essential condition leading to the adult atherosclerotic plaque formation. Owing to the difficulty to study the SMC regulation in vivo, most of the literature in this field refers to in vitro models. Modulated SMC in culture, changing from a contractile to a synthetic state, share similar features with atherosclerotic plaques cells. The phenotypic modulation of SMC is expressed by morphological, biochemical, metabolic and functional modifications. The regulation of cholesterol movements might influence the foam transformation process of arterial SMC. |
| Modulation of ATPase activity by cholesterol and synthetic ether lipids in leukemic cells Diomede, L., R. Bianchi, et al. (1992), Biochem Pharmacol 43(4): 803-7. Abstract: Synthetic ether lipids (EL) exert their antiproliferative action on leukemic cells through localization in the plasma membrane with subsequent biochemical effects which are still being elucidated. In the present study, the modulation of membrane-linked ATPase activity was investigated in relation to changes in membrane fluidity of HL60 and K562 human leukemic cells. Incubation of HL60 and K562 cells with EL under non-cytotoxic conditions caused significant membrane fluidization which was related to the membrane cholesterol (CHOL) levels. HL60 cells, which are sensitive to the cytotoxic action of EL, had a lower basal CHOL content. When HL60 cells were loaded with CHOL, Na+, K(+)-ATPase activity was reduced significantly compared to that of untreated cells. In contrast, CHOL-deprived K562 cells had twice the Na+,K(+)-ATPase activity of unmodified K562 cells. Na+K(+)- and Mg(2+)-ATPase activities were stimulated significantly in both cell lines by EL at concentrations lower than 20 microM. This stimulation was greater in cells richer in CHOL, such as K562 cells and CHOL-enriched HL60 cells. In contrast, Na+,K(+)-ATPase in both cell lines was inhibited by EL above 20 microM regardless of the CHOL content. Mg(2+)-ATPase activity was not related to cell CHOL content and was not inhibited by EL above 20 microM. |
| Modulation of cellular cholesterol alters P-glycoprotein activity in multidrug-resistant cells Troost, J., H. Lindenmaier, et al. (2004), Mol Pharmacol 66(5): 1332-9. Abstract: The drug transporter P-glycoprotein (ABCB1) plays an important role in drug distribution and elimination, and when overexpressed it may confer multidrug resistance (MDR). P-glycoprotein is localized in the plasma membrane, especially within rafts and caveolae, characterized as detergent-resistant membranes (DRMs). This study investigated the effect of cholesterol depletion and repletion as well as saturation on subcellular localization and function of P-glycoprotein to determine the effect of DRM localization on P-glycoprotein-mediated drug efflux. In L-MDR1 overexpressing human P-glycoprotein, cholesterol depletion removed P-glycoprotein from the raft membranes into non-DRM fractions, whereas repletion fully reconstituted raft localization. P-glycoprotein function was assessed by realtime monitoring with confocal laser scanning microscopy using BODIPY-verapamil as substrate. Cholesterol depletion reduced P-glycoprotein function in L-MDR1 cells resulting in intracellular substrate accumulation (159% +/- 43, p < 0.001; control = 100%). Cholesterol repletion reduced intracellular substrate fluorescence (120% +/- 36, p < 0.001) and restored the transporter activity. Addition of surplus cholesterol (saturation) even enhanced drug efflux in L-MDR1 cells, leading to reduced intracellular accumulation of BODIPY-verapamil (69% +/- 10, p < 0.001). Transport of BODIPY-verapamil in cells not expressing human P-glycoprotein (LLC-PK1) was not susceptible to cholesterol alterations. These results demonstrate that cholesterol alterations influence P-glycoprotein localization and function, which might contribute to the large interindividual variability of P-glycoprotein activity known from in vivo studies. |
| Modulation of cellular cholesterol and its effect on cornified envelope formation in cultured human epidermal keratinocytes Schmidt, R., E. J. Parish, et al. (1991), J Invest Dermatol 97(5): 771-5. Abstract: When cultured human epidermal keratinocytes (NHK) reach confluence they start to differentiate and an increase in the total cellular cholesterol content is observed. This increase parallels the appearance of a characteristic feature of terminal keratinocyte differentiation, the spontaneous formation of cornified envelopes (CE). Synthesis of CE is catalyzed by the plasma membrane-associated transglutaminase (TGm). Supplementation of the medium with inhibitors of cholesterologenesis suppressed increase in cholesterol levels and CE formation but did not interfere with TGm expression or TGm activity. Modulation of the plasma membrane cholesterol-phospholipid ratio of confluent NHK cultures using either pure phospholipid liposomes or liposomes enriched in cholesterol strongly affected spontaneous CE formation. Pure phospholipid liposomes completely inhibited CE formation, whereas cholesterol-enriched liposomes ensured envelope formation, even in the presence of inhibitors of cholesterol synthesis. From these results we conclude that in differentiating NHK an increase in the cellular cholesterol level is part of the differentiation program and is essential for the spontaneous CE formation. |
| Modulation of cellular cholesterol transport and homeostasis by Rab11 Holtta-Vuori, M., K. Tanhuanpaa, et al. (2002), Mol Biol Cell 13(9): 3107-22. Abstract: To analyze the contribution of vesicular trafficking pathways in cellular cholesterol transport we examined the effects of selected endosomal Rab proteins on cholesterol distribution by filipin staining. Transient overexpression of Rab11 resulted in prominent accumulation of free cholesterol in Rab11-positive organelles that sequestered transferrin receptors and internalized transferrin. Sphingolipids were selectively redistributed as pyrene-sphingomyelin and sulfatide cosequestered with Rab11-positive endosomes, whereas globotriaosyl ceramide and GM2 ganglioside did not. Rab11 overexpression did not perturb the transport of 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine-perchlorate-labele d low-density lipoprotein (LDL) to late endosomes or the Niemann-Pick type C1 (NPC1)-induced late endosomal cholesterol clearance in NPC patient cells. However, Rab11 overexpression inhibited cellular cholesterol esterification in an LDL-independent manner. This effect could be overcome by introducing cholesterol to the plasma membrane by using cyclodextrin as a carrier. These results suggest that in Rab11-overexpressing cells, deposition of cholesterol in recycling endosomes results in its impaired esterification, presumably due to defective recycling of cholesterol to the plasma membrane. The findings point to the importance of the recycling endosomes in regulating cholesterol and sphingolipid trafficking and cellular cholesterol homeostasis. |
| Modulation of cholesterol concentration in Caco-2 cells by incubation with different n-6 fatty acids Koba, K., J. W. Liu, et al. (2000), Biosci Biotechnol Biochem 64(12): 2538-42. Abstract: Incorporation of exogenous cholesterol was compared in human adenocarcinoma colon cells (Caco-2) after incubation with 100 microM of either linoleic acid (LA, 18:2n-6), gamma-linolenic acid (GLA, 18:3n-6), arachidonic acid (AA, 20:4n-6) or adrenic acid (or n-6 docosatetraenoic acid, DTA, 22:4n-6). In both cells 7 days after seeding and 14 days after confluency, incubation with LA significantly raised the proportion of 18:2n-6 but not its long-chain metabolites in cellular phospholipid. Incubation with GLA increased the levels of 18:3n-6, 20:3n-6, and 20:4n-6. Incubation with AA increased the levels of 20:4n-6 and 22:4n-6, and incubation with DTA increased the levels of 22:4n-6 as well as its retro-conversion metabolite, 20:4n-6. A subsequent addition of cholesterol (180 microM) to the medium significantly raised the cellular cholesterol level but less so in the cells 7 days after seeding incubated with GLA. The increase in cellular cholesterol level was generally greater in the cells of 7 days after seeding, particularly those incubated with long-chain highly unsaturated n-6 fatty acids, than in those of 14 days after confluency. These findings suggest that the cell growth and the extent of unsaturation in cell membrane phospholipid fatty acids modulate the incorporation of the exogenous cholesterol into the Caco-2 cells. |
| Modulation of cholesterol crystallization in bile. Implications for non-surgical treatment of cholesterol gallstone disease Portincasa, P., A. Moschetta, et al. (2005), Curr Drug Targets Immune Endocr Metabol Disord 5(2): 177-84. Abstract: The first step in cholesterol gallstone disease is precipitation of cholesterol crystals in bile. In gallbladder bile. cholesterol is normally solubilized together with bile salts and phospholipids to form mixed micellar structures. When cholesterol in bile is in excess, vesicles (i.e. phospholipid-cholesterol globular structures: liquid crystals) form which become supersaturated in cholesterol. Early aggregation and precipitation of cholesterol molecules into submicroscopic nuclei occurs from these supersaturated vesicles. This crucial step is followed by precipitation and agglomeration of cholesterol crystals which then become visible at light microscopy. Here we describe the mechanism of cholesterol crystallization and its modulation in vivo and in vitro. Recent advances on the role of ursodeoxycholate as an agent preventing the precipitation of cholesterol crystals in bile will be highligthed. |
| Modulation of cholesterol efflux from Fu5AH hepatoma cells by the apolipoprotein content of high density lipoprotein particles. Particles containing various proportions of apolipoproteins A-I and A-II Lagrost, L., C. Dengremont, et al. (1995), J Biol Chem 270(22): 13004-9. Abstract: The influence of apolipoproteins (apo) A-I and A-II on the ability of high density lipoproteins (HDL) to remove cholesterol from cultured Fu5AH rat hepatoma cells was studied independently on alterations in the overall structure and lipid composition of the lipoprotein particles. To this end, apoA-I was progressively replaced by apoA-II in ultracentrifugally isolated HDL3 without inducing changes in other remaining lipoprotein components. As apoA-II was progressively substituted for apoA-I in HDL3 (A-II:A-I+A-II percentage mass: 29.5, 47.6, 71.5, 97.4, and 98.9%), the rate of cholesterol efflux from Fu5AH hepatoma gradually and significantly decreased after 2 or 4 h of incubation at 37 degrees C (cholesterol efflux: 30.4 +/- 0.8, 24.1 +/- 1.0, 19.8 +/- 1.2, 15.7 +/- 1.4, and 13.4 +/- 1.3%/2h, respectively; 38.4 +/- 1.5, 29.2 +/- 0.9, 27.0 +/- 0.2, 20.4 +/- 0.4, and 17.5 +/- 1.0%/4h, respectively) (p < 0.01 with all A-II-enriched HDL3 fractions as compared with non-enriched homologues). In agreement with data obtained with total HDL3, increasing the A-II:A-I+A-II percentage mass in HDL3 particles containing initially only apoA-I (HDL3-A-I) progressively reduced cellular cholesterol efflux. After 2 h of incubation, cholesterol efflux correlated negatively with A-II:A-I+A-II percentage mass (r = -0.86; p < 0.0001; n = 20), but not with either free cholesterol:phospholipid ratio, A-I+A-II:total lipid ratio or mean size of HDL3. As determined by using Spearman rank correlation analysis, the A-II:A-I+A-II% mass ratio correlated negatively with the apparent maximal efflux (Vmax(efflux)) (rho = -0.68; p < 0.05, n = 10), but not with the HDL3 concentration required to obtain 50% of maximal efflux (Km(efflux)) (rho = -0.08; not significant, n = 10). It was concluded that the apoA-I and apoA-II content of HDL3 is one determinant of its ability to promote cholesterol efflux from Fu5AH rat hepatoma cells. |