| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Cubic phase is induced by cholesterol in the dispersion of 1-palmitoyl-2-oleoyl-phosphatidylethanolamine Wang, X. and P. J. Quinn (2002), Biochim Biophys Acta 1564(1): 66-72. Abstract: The effect of cholesterol, a major constituent of eukaryotic cell membranes, on the structure and thermotropic phase behaviour of 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE) dispersed in excess water was examined by synchrotron X-ray diffraction methods. Temperature scans over the range 10-75 degrees C showed that the gel to liquid-crystalline phase transition decreased from 25 to 10 degrees C in the presence of 20 mol% cholesterol, and no gel phase could be detected in the wide-angle X-ray scattering (WAXS) intensity profile of mixtures containing 35 mol% cholesterol. The small-angle X-ray scattering (SAXS) intensity profiles showed that the lamellar to nonlamellar phase transition temperature was also decreased in mixtures containing up to 30 mol% cholesterol but the trend was reversed in mixtures containing a higher proportion of cholesterol. There was evidence that the transition of the lamellar liquid-crystal phase is to cubic phases in mixtures containing less than 30 mol% cholesterol. The space group of one of these cubic phases was assigned as Pn3m. This effect of cholesterol on non-bilayer-forming phospholipids is considered in the context of the role of cholesterol in membrane organization and function. |
| Cultured fibroblasts from patients with Niemann-Pick disease type C and type D exhibit distinct defects in cholesterol esterification Sidhu, H. S., S. A. Rastogi, et al. (1992), Biochim Biophys Acta 1124(1): 29-35. Abstract: The Niemann-Pick group of diseases can be broadly classified into two types based on clinical and biochemical characteristics. Type I is characterized by a primary deficiency of lysosomal sphingomyelinase while Type II may have a defect in the regulation of intracellular cholesterol metabolism. We have studied cholesterol esterification in cultured fibroblasts from patients with two phenotypes of Type II disease: an Acadian population of southwestern Nova Scotia (Canada) with a form of the disease known as Niemann-Pick type D (NPD) and a group of panethnic origin with Niemann-Pick type C (NPC). Addition of whole serum to normal fibroblasts grown initially in lipoprotein-deficient serum caused a rapid (within 6 h) increase in cholesterol esterification, reaching maximum values at around 24 h, while NPC fibroblasts showed little increase (less than 10% of normal). In contrast, cholesterol esterification in NPD fibroblasts increased slowly during the first 6-12 h and reached 50% of normal values by 24 h. 25-Hydroxycholesterol, a non-lipoprotein stimulator of cholesterol esterification, caused a similar stimulation of cholesterol esterification in NPC, NPD and normal cells. This was inhibited by addition of serum in mutant but not in normal cells. Within 24 h of serum addition, free cholesterol accumulated in all cell types with NPC greater than NPD greater than normal. These observations indicate that (a) regulation of cholesterol esterification in response to serum lipoproteins (but not 25-hydroxycholesterol) is abnormal in both NPC and NPD fibroblasts, and (b) the biochemical phenotypes of fibroblasts from NPC and NPD patients are distinct. |
| Current concepts in cardiovascular pathology: the role of LDL cholesterol in plaque rupture and stabilization Libby, P., U. Schoenbeck, et al. (1998), Am J Med 104(2A): 14S-18S. Abstract: Emerging evidence is redefining traditional concepts of coronary atherosclerosis. Recent data indicate that severe stenoses, the traditional focus of attention, do not cause most coronary events. Rather, interest has increased in the often less stenotic but more vulnerable lesions that are characterized by thin fibrous caps, large lipid accumulations, large numbers of macrophages, and depletion of smooth muscle cells. Such lesions appear prone to rupture, which allows the blood to come into contact with the highly thrombogenic material in the lipid core of the plaque, thereby precipitating thrombosis. The fibrous cap may become weakened through decreased synthesis of the extracellular matrix or increased degradation of the matrix. The cytokine interferon-gamma, produced by T-lymphocytes, inhibits the ability of smooth muscle cells to synthesize collagen, a structurally important component of the fibrous cap. A family of enzymes known as matrix metalloproteinases can degrade all major constituents of the vascular extracellular matrix: collagen, elastin, and proteoglycans. Additional studies on the biochemical mechanisms of atherosclerosis may provide a fuller understanding of the ways in which lipid-lowering therapy can confer clinical benefit. |
| Current concepts in cholesterol gallstone pathogenesis Busch, N. and S. Matern (1991), Eur J Clin Invest 21(5): 453-60. |
| Current concepts of cholesterol transport and crystal formation in human bile Holzbach, R. T. (1990), Hepatology 12(3 Pt 2): 26S-31S; discussion 31S-32S. Abstract: The presence of vesicles in human bile probably accounts almost entirely for the frequently observed, but hitherto unexplained, phenomenon of metastable cholesterol supersaturation. This, in turn, largely explains the prolonged stability of cholesterol solubilized in supersaturated human bile. Under certain overall compositional conditions for a supersaturated native bile, the vesicular phase in its contribution to total cholesterol transport also becomes supersaturated in cholesterol. Because of this, the vesicles also become unstable, leading to formation of cholesterol crystals. A simple but common example of one factor affecting composition in this way is concentration of total solutes, especially the biliary lipids. Conversely, dilution of bile (e.g., hepatic bile) markedly reduces the cholesterol saturation level in biliary vesicles. The result is that such vesicles become much more stable. Under these conditions, cholesterol crystal formation becomes unlikely and rarely, if ever, occurs. |
| Current controversies in screening: cholesterol, breast cancer, and prostate cancer Sox, H. C. (1999), Mt Sinai J Med 66(2): 91-101. Abstract: Physicians must make decisions in day-to-day practice even when the balance of benefit and harm is not yet known. Adopting a clinical policy about screening is a case in point. Three controversies in screening healthy adults illustrate different aspects of resolving a dispute when the evidence is incomplete. The major controversy in cholesterol screening is whether to screen young adults. There has never been a randomized trial of treatment, let alone a trial of screening, in young adults. However, a patchwork of evidence strongly suggests that, because the baseline risk of coronary heart disease (CHD) is very small in young adults, the absolute reduction in risk from treatment would be very small. In breast cancer screening, randomized trials do not show conclusively that periodic mammography for women aged 40-49 years reduces breast cancer mortality. A 7-10 year delay between the first mammogram and a reduction in deaths from breast cancer suggests the hypothesis that the only benefit of screening women aged 40-49 years occurs from mammograms performed after age 50. There is no high quality evidence that early detection and treatment reduce the death rate from prostate cancer. In lieu of randomized trial data, we must depend on a decision analysis that shows that screening middle-aged men is cost-effective relative to other preventive services. However, this result depends on using optimistic survival data in the decision model, and most organizations do not recommend routine screening. The best strategy is to discuss the harms and benefits, and let the patient decide. |
| Current lipid management and low cholesterol goal attainment in common daily practice in Spain. The REALITY Study Garcia Ruiz, F. J., A. Marin Ibanez, et al. (2004), Pharmacoeconomics 22 Suppl 3: 1-12. Abstract: OBJECTIVE: To evaluate prescribing patterns of lipid-lowering drugs used in management of patients at risk of coronary heart disease (CHD) in usual clinical practice in Spain and to assess low-density lipoprotein cholesterol (LDL-C) goal attainment among CHD and CHD equivalent patients (< 100 mg/dL) and non-CHD patients with two or more risk factors (< 130 mg/dL) who were prescribed lipid-lowering drugs. METHODS: Cohort study with retrospective chart review at 23 primary care centres and 16 lipid treatment centres across Spain (59% primary care; 41% outpatient lipid centres). Physicians consecutively identified eligible patients. Adults (aged > or = 18 years) with CHD/CHD equivalent or two or more major risk factors prior to first prescription of lipid-lowering drugs were eligible. Medical records were reviewed by physicians to collect patient characteristics, baseline and follow-up laboratory values and lipid-lowering drug treatment data. RESULTS: 619 patients (45.5% CHD and CHD equivalent patients and 54.5% non-CHD with two or more major risk factors) were included in the study with an average study follow-up of 3.6 years. Mean age was 60.1 years (SD 10.2), and 47.8% were female. Mean baseline LDL-C was 178 mg/dL (SD 45.0) for the CHD/CHD equivalent patients and 191 mg/dL (SD 56.95) for patients with two or more risk factors. Statins were the initial lipid-lowering drugs in 90.2% of patients; 52.5% of patients were initiated on low-dose (simvastatin 10mg or lower potency) statins. Overall 20.2% of CHD/CHD equivalent and 31.4% of patients with two or more risk factors attained LDL-C goal during the study period; of patients not attaining goal, 28.7% required an additional LDL-C reduction of > 30% to attain goal. In a logistic regression model for goal attainment, CHD/CHD equivalent patients (odds ratio OR 0.47; 95% confidence interval CI 0.31, 0.72) and patients with baseline LDL-C > 190 mg/dL (OR 0.53; 95% CI 0.35, 0.80) were least likely to reach cholesterol goal when compared with patients having baseline LDL-C > 100 mg/dL and < 130 mg/dL. Conclusion: Only 12.9% of patients attained LDL-C goal on their initial lipid-lowering drugs, and an additional 13.4% achieved goal after a change in their lipid-lowering therapy, resulting in 73.7% of patients not attaining goal after at least 3 years of follow-up, after initiation of lipid-lowering therapy. Patients who would gain the most from aggressive lipid lowering (CHD patients and patients with high baseline LDL-C) were least likely to achieve goal. More effective lipid management is needed to help these patients lower their cholesterol to goal levels or even lower. |
| Current practice in low-density lipoprotein-cholesterol measurements for the clinical management of hyperlipidemia Nakamura, Y., T. Miida, et al. (2003), J Cardiol 42(6): 261-8. Abstract: OBJECTIVES AND METHODS: Low-density lipoprotein cholesterol (LDL-C) measurements in clinics were evaluated by a multiple-choice questionnaire sent to 146 physicians (78 general practitioners and 68 hospital physicians) in Niigata Prefecture, Japan. RESULTS: Seventy-six percent of the general practitioners and 84% of the hospital staff measured LDL-C, and 60% of all physicians calculated LDL-C using the Friedewald formula. Sixty-two percent of general practitioners and 43% of hospital physicians took blood samples without overnight fasting and 40-50% of whom estimated LDL-C using the Friedewald formula, although the formula is reliable only for samples collected after an overnight fast. Two thirds of the physicians managed patients according to the Japan Atherosclerosis Society Guidelines (1997), whereas 40-50% based diagnoses and treatments on total cholesterol, and only 20-30% used LDL-C-based management. CONCLUSIONS: Direct measurement, education and management of LDL-C not affected by diet are mandatory. |
| Current status of cholesterol treatment in the community: the Minnesota Heart Survey Luepker, R. V. (1997), Am J Med 102(2A): 37-42. Abstract: There is a consensus on the importance of lowering blood cholesterol in individuals and populations. To determine trends in the detection and treatment of elevated cholesterol, a series of studies known as the Minnesota Heart Survey evaluated cardiovascular disease, risk, and health behavior among adults in the upper Midwest between 1980 and 1992. Over 25,000 adult residents of large and small communities were surveyed for information on risk factors and health habits, including status of cholesterol detection and treatment. During those years, population levels of blood cholesterol declined significantly for both men and women, largely as the result of changes in diet. Levels of clinical detection of hypercholesterolemia, initially low, also rose. However, subjects who had been informed that they had increased lipids reported that recommendations from their physicians for dietary therapy declined, while recommendations for weight loss increased during the survey period. Medication use for elevated blood cholesterol, always low, rose slightly, but many subjects discontinued medications due to side effects, the perception that their cholesterol was controlled, lack of perceived benefit, or cost. A total of 274 primary care physicians were also surveyed. Physicians reported that they screen more frequently than in the past and initiate drug therapy at a lower threshold. Despite improving trends in detection, treatment, and follow-up for elevated blood cholesterol in the general population, > 50% of U.S. citizens are still unaware of their elevated cholesterol levels and a growing segment of the population that has been identified as having elevated blood cholesterol remains untreated. Dietary therapy needs to be better utilized. Physicians also need to educate their patients about the importance of maintaining desirable cholesterol levels and to encourage compliance with medications for those who require them. |
| Cutaneous microvascular responses are improved after cholesterol-lowering in patients with peripheral vascular disease and hypercholesterolaemia Khan, F., S. J. Litchfield, et al. (1997), Adv Exp Med Biol 428: 49-54. |
| CXCR4 function requires membrane cholesterol: implications for HIV infection Nguyen, D. H. and D. Taub (2002), J Immunol 168(8): 4121-6. Abstract: HIV requires cholesterol and lipid rafts on target cell membranes for infection. To elucidate a possible mechanism, we determined that cholesterol extraction by hydroxypropyl-beta-cyclodextrin (BCD) inhibits stromal cell-derived factor 1alpha (SDF-1alpha) binding to CXCR4 on T cell lines and PBMCs. Intracellular calcium responses to SDF-1alpha, as well as receptor internalization, were impaired in treated T cells. Loss in ligand binding is likely due to conformational changes in CXCR4 and not increased sensitivity to internalization. SDF-1alpha binding and calcium responses were effectively restored by reloading cholesterol. Immunofluorescence microscopy revealed that SDF-1alpha binding occurred in lipid raft microdomains that contained GM1. CXCR4 surface expression, on the other hand, only partially colocalized with GM1. HIV-1(IIIB) infection assays confirmed the functional loss of CXCR4 in the cell lines tested, Sup-T1 and CEM-NKR-CCR5. These data suggest that cholesterol is essential for CXCR4 conformation and function and that lipid rafts may play a regulatory role in SDF-1alpha signaling. |
| Cyclic AMP analogues stimulate triacylglycerol synthesis but not cholesterol esterification in J774 macrophages Jones, A. K., B. Jackson, et al. (1996), Biochem Soc Trans 24(3): 440S. |
| Cyclic AMP and the regulation of cholesterol metabolism Botham, K. M. (1992), Biochem Soc Trans 20(2): 454-9. Abstract: Cyclic AMP has been implicated to a greater or lesser extent in the regulation of four key enzymes which interact to regulate intracellular cholesterol metabolism; HMG CoA reductase; ACAT; cholesteryl ester hydrolase; and cholesterol 7 alpha hydroxylase. The relationship between these enzymes and the sites where current evidence suggests that cyclic AMP may be involved are summarized in Fig. 3. Cholesterol 7 alpha hydroxylase controls the catabolism of cholesterol to bile acids in the liver, and thus its removal from the body via the bile, but does not have a major role in cholesterol metabolism in extrahepatic tissues. It is clear that cyclic AMP is able to influence the activity of this enzyme in liver sub-cellular fractions and isolated hepatocytes in vitro, and studies in our laboratory have shown that changes in Ca2+ fluxes within the cell may be important in its mechanism of action. Whether or not the cyclic nucleotide has a role regulating cholesterol 7 alpha hydroxylase activity in vivo, however, is not known. HMG CoA reductase is inactivated by phosphorylation both in vitro and in vivo, but although cyclic AMP and glucagon have been shown to inhibit the enzyme, cyclic AMP-dependent protein kinase is not directly involved. The exact mechanism by which the cyclic nucleotide influences the system remains unclear, but it may be related to activation of microsomal phosphatases. The activity of ACAT has been shown to be modulated by phosphorylation in a number of tissues in vitro, but the involvement of cyclic AMP has not been unequivocally demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Cyclic AMP induces apolipoprotein E binding activity and promotes cholesterol efflux from a macrophage cell line to apolipoprotein acceptors Smith, J. D., M. Miyata, et al. (1996), J Biol Chem 271(48): 30647-55. Abstract: RAW 264 mouse macrophage cells were stably transfected with human apolipoprotein E (apoE) expression vectors. Clonal derivatives were characterized for expression of the human apoE2, apoE3, and apoE4 isoforms. An apoE4-expressing clonal cell line and a non-expressing clonal control cell line were loaded overnight with either 3Hcholesterol or 3Hcholine. The cells were washed and incubated for 24 h in serum-free medium with or without the addition of 8-bromo-cyclic AMP (8-Br-cAMP). Only the apoE-secreting cells and only in the presence of 8-Br-cAMP released large amounts of labeled cholesterol or phosphatidylcholine into the medium. Mass analyses of cellular free and esterified cholesterol confirmed the results of the labeling studies; a decrease in cellular cholesterol content was observed in the 8-Br-cAMP-treated apoE-secreting cells, concurrent with an increase in cholesterol found in the medium. FPLC analysis of the medium demonstrated that 8-Br-cAMP treatment of the apoE-secreting cells led to an increased size fraction and amount of a peak of secreted cholesterol which comigrated with apoE. The 8-Br-cAMP-mediated increase in cholesterol efflux was also observed in non-apoE-secreting cells incubated with exogenous apoE or apoAI, and the effect of apoE was saturable. The apoE2, apoE3, and apoE4 isoforms were equally efficient in promoting 8-Br-cAMP-dependent cholesterol efflux. Reductive methylation of apoE abolished its ability to promote 8-Br-cAMP-dependent cholesterol efflux. Brefeldin A and monensin, inhibitors of protein processing through the Golgi, both blocked the 8-Br-cAMP stimulation of cholesterol efflux to exogenous apoE. 8-Br-cAMP induced specific apoE and apoAI binding, but not apoE degradation, by the RAW cells. We present a model wherein cAMP induces a membrane apolipoprotein receptor that does not lead to endocytosis and degradation, but instead promotes the transfer of lipids to apolipoproteins, which can then be released from the cell. |
| Cyclic AMP stimulates efflux of intracellular sterol from cholesterol-loaded cells Hokland, B. M., J. P. Slotte, et al. (1993), J Biol Chem 268(34): 25343-9. Abstract: The interaction of high density lipoprotein with its putative receptor stimulates translocation and efflux of intracellular sterols by a process involving activation of protein kinase C. This study shows that activation of cAMP-dependent protein kinase also stimulates efflux of intracellular sterols. When intracellular sterol pools of cholesterol-loaded cultured human skin fibroblasts and bovine aortic endothelial cells were radiolabeled with the biosynthetic precursor 3Hmevalonolactone, high density lipoprotein3 (HDL3)-mediated 3H-sterol efflux was enhanced by addition of the adenylylcyclase activator forskolin, the phosphodiesterase inhibitors theophylline and 3-isobutyl-1-methylxanthine, and the cAMP analogues N6-benzoyl-cAMP (N6-cAMP) and 8-thiomethyl-cAMP. The effect of N6-cAMP was abolished by an inhibitor of cAMP-dependent protein kinase (H8). The enhanced sterol efflux was independent of receptor binding of HDL3, as similar effects were observed in the presence of tetranitromethane-modified HDL3, which lacks receptor binding activity. N6-cAMP stimulated efflux of several subspecies of newly synthesized sterols, including cholesterol. Elevation of cAMP levels increased the proportion of radiosterols that were accessible to treatment of cells with the enzyme cholesterol oxidase, suggesting that activation of cAMP-dependent protein kinase stimulates translocation of sterols from intracellular compartments to the plasma membrane where they desorb from the cell surface. Thus, at least two distinct protein kinase signalling pathways modulate transport of intracellular sterols in cholesterol-loaded cells. |
| Cyclic AMP-specific phosphodiesterase 4 inhibitors promote ABCA1 expression and cholesterol efflux Lin, G. and K. E. Bornfeldt (2002), Biochem Biophys Res Commun 290(2): 663-9. Abstract: ATP cassette binding protein 1 (ABCA1) controls the apolipoprotein-mediated cholesterol efflux pathway and determines plasma HDL levels. Although cAMP is known to promote ABCA1 expression and cholesterol efflux from cells, it has not been determined whether cyclic nucleotide phosphodiesterase (PDE) isoforms regulate this pathway. We show that rolipram and cilomilast, inhibitors of cAMP-specific PDE4, increase apolipoprotein A-I (apoA-I)-mediated cholesterol efflux up to 80 and 140% in human THP-1 and mouse J774.A1 macrophages, respectively, concomitant with an elevation of cAMP levels. The EC(50) value was estimated to be 1 to 2 microM for both inhibitors. Rolipram and cilomilast also increase ABCA1 protein expression in THP-1 and J774.A1 macrophages. Thus, PDE4 inhibitors cause parallel increases in cAMP levels, ABCA1 expression and apoA-I-mediated cholesterol efflux. PDE4 inhibitors may provide a novel strategy for the treatment of cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions. |
| Cyclodextrin removes cholesterol from mouse sperm and induces capacitation in a protein-free medium Choi, Y. H. and Y. Toyoda (1998), Biol Reprod 59(6): 1328-33. Abstract: Cyclodextrin, which stimulates cholesterol efflux from cells, was examined for its ability to induce capacitation of mouse spermatozoa. A chemically defined, protein-free medium was used for in vitro fertilization of cumulus-free mouse eggs. Fertilization did not occur in modified Krebs-Ringer bicarbonate medium (TYH) supplemented with 1 mg/ml polyvinylalcohol instead of BSA. However, fertilization was observed when spermatozoa were preincubated with methyl-beta-cyclodextrin (MBCD); fertilization rates increased dose-dependently from 0.25 to 0.75 mM MBCD. The fertilization rate decreased when 0.75 mM MBCD was added to both preincubation and fertilization media versus only the preincubation medium (21% vs. 53%); in sharp contrast, fertilization increased when 4 mg/ml BSA was present in both of the media versus the preincubation medium only (66% vs. 25%). At 0.75 mM, 2-hydroxy-beta-cyclodextrin had a lower ability to capacitate spermatozoa in vitro than MBCD (14% vs. 41%). Eggs fertilized by spermatozoa treated with MBCD (0.75 mM) developed to blastocysts (45%, 36 of 80) when cultured in KSOM. When 160 fertilized eggs were transferred to ICR recipients, 62 live offspring were born. After incubation of mouse spermatozoa for 90 min in 0.75 mM MBCD in TYH medium, the cholesterol content of the spermatozoa was significantly (p < 0.01) lower than that of the control (2.27 +/- 0.09 vs. 4.13 +/- 0.09 nmol unesterified cholesterol/10(7) sperm; mean +/- SEM, n = 5). The proportion of capacitated (B pattern) spermatozoa determined by chlortetracycline fluorescence was higher with MBCD treatment for 90 min than for the control (45% vs. 15%; p < 0.01). The proportion of acrosome-reacted (AR pattern) spermatozoa was not different between MBCD treatment and the control. Therefore, MBCD increased capacitation rather than the acrosome reaction of spermatozoa. |
| Cyclodextrins as carriers of cholesterol and fatty acids in cultivation of mycoplasmas Greenberg-Ofrath, N., Y. Terespolosky, et al. (1993), Appl Environ Microbiol 59(2): 547-51. Abstract: The design of fully or partly defined media for mycoplasma cultivation involves the need to provide the essential lipids, cholesterol and long-chain fatty acids, in an assimilable and nontoxic form. This study introduces cyclodextrins (CDs) as carriers of these lipids, thus suggesting alternatives to serum or bovine serum albumin (BSA). The effects of beta-CD and two forms of chemically modified beta-CD, dimethyl-beta-CD (Dimeb) and hydroxypropyl-beta-CD (Hyprob), on the growth of Mycoplasma capricolum and Acholeplasma laidlawii were investigated in a basal medium as well as in serum- and BSA-supplemented media. beta-CD was found to inhibit the growth of the sterol-requiring M. capricolum in both serum and BSA media, but it stimulated the growth of the sterol-independent A. laidlawii. Inhibition by beta-CD was explained by its capacity to form a water-insoluble CD-cholesterol complex, thus rendering it unavailable to the cells. Dimeb, despite its strong complexing ability for lipids, was found to be toxic to all mycoplasma species in both liquid cultures and agar diffusion susceptibility tests. In sharp contrast to beta-CD and Dimeb, Hyprob (with a degree of substitution of 4.2) added at 5 and 10 mM to a basal medium supplemented with lipids permitted growth of M. capricolum. Comparison of growth curves in the two conventional serum and BSA media with those in two Hyprob media revealed comparable growth and growth rates. |
| Cyclodextrins as catalysts for the removal of cholesterol from macrophage foam cells Atger, V. M., M. de la Llera Moya, et al. (1997), J Clin Invest 99(4): 773-80. Abstract: Low concentrations of cyclodextrins (< 1.0 mM) added to serum act catalytically, accelerating the exchange of cholesterol between cells and lipoproteins. J774 macrophages incubated with serum and 2-hydroxypropyl-beta-cyclodextrin (< or = 1 mM) released fivefold more labeled cholesterol than with serum alone. Increased efflux was not accompanied by a change in cell cholesterol mass; thus, cyclodextrin functioned as a cholesterol shuttle, enhancing cholesterol bidirectional flux without changing the equilibrium cholesterol distribution between cells and medium. The addition of phospholipid vesicles to serum and cyclodextrin shifted the equilibrium distribution to favor the medium, producing rapid and extensive depletion of cell cholesterol mass. The combination of serum, phospholipid vesicles, and cyclodextrin also stimulated the rapid clearance of both free and esterified cholesterol from mouse peritoneal macrophages loaded with free and esterified cholesterol. This study: (a) demonstrates that a compound can function as a catalyst to enhance the movement of cholesterol between cells and serum, (b) illustrates the difference between cholesterol exchange and net transport in a cell/serum system, (c) demonstrates how net movement of cholesterol is linked to concentration gradients established by phospholipids, (d) provides a basis for the development of the shuttle/sink model for the first steps in reverse cholesterol transport, (e) validates the model using artificial shuttles (cyclodextrins) and sinks (large unilamellar vesicles), and (f) suggests that cyclodextrin-like cholesterol shuttles might be of pharmacological significance in treating unstable atherosclerotic plaques. |
| Cyclodextrins differentially mobilize free and esterified cholesterol from primary human foam cell macrophages Liu, S. M., A. Cogny, et al. (2003), J Lipid Res 44(6): 1156-66. Abstract: Human monocyte-derived foam cell macrophages (HMFCs) are resistant to cholesterol efflux mediated by physiological acceptors. The role of the plasma membrane in regulating depletion of free cholesterol (FC) and of cholesteryl ester (CE) was investigated using cyclodextrins (CDs). HMFCs were incubated in media containing CDs (1.0 mg/ml, approximately 0.7 mM) with low hydroxypropyl-beta-CD (HP-CD) or high trimethyl-beta-CD (TM-CD) affinity for cholesterol in the presence or absence of phospholipid vesicles (PLVs). Low-affinity HP-CD caused minimal cholesterol efflux on its own, but HP-CD+ PLV depleted cell FC and CE to 54.5 +/- 6.7% of control by 24 h. TM-CD depleted FC at least as well as HP-CD+PLV but without depleting CE, even when combined with PLV. This was not explained by acceptor saturation, instability of PLV vesicles, de novo cholesterol synthesis, kinetically distinct cholesterol pools, or inhibition of CE hydrolysis. TM-CD did, however, deplete CE when lower concentrations of TM-CD were combined with PLV and when acetyl-CoA cholesteryl acyltransferase was inhibited. TM-CD caused much greater depletion of plasma membrane cholesterol than HP-CD without depleting plasma membrane sphingomyelin. It is concluded that differential depletion of plasma membrane cholesterol pools regulates cholesterol efflux and CE clearance in human macrophages. |