| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| MLN64 mediates mobilization of lysosomal cholesterol to steroidogenic mitochondria Zhang, M., P. Liu, et al. (2002), J Biol Chem 277(36): 33300-10. Abstract: This study demonstrates that the steroidogenic acute regulatory protein-related lipid transfer (START) domain-containing protein, MLN64, participates in intracellular cholesterol trafficking. Analysis of the intracellular itinerary of MLN64 and MLN64 mutants tagged with green fluorescent protein showed that the N-terminal transmembrane domains mediate endocytosis of MLN64 from the plasma membrane to late endocytic compartments. MLN64 constitutively traffics via dynamic NPC1-containing late endosomal tubules in normal cells; this dynamic movement was inhibited in cholesterol-loaded cells, and MLN64 is trapped at the periphery of cholesterol-laden lysosomes. The MLN64 START domain stimulated free cholesterol transfer from donor to acceptor mitochondrial membranes and enhanced steroidogenesis by placental mitochondria. Expression of a truncated form of MLN64 (DeltaSTART-MLN64), which contains N-terminal transmembrane domains but lacks the START domain, caused free cholesterol accumulation in lysosomes and inhibited late endocytic dynamics. The DeltaSTART-MLN64 dominant negative protein was located at the surface of the cholesterol-laden lysosomes. This dominant negative mutant suppressed steroidogenesis in COS cells expressing the mitochondrial cholesterol side chain cleavage system. We conclude that MLN64 participates in mobilization and utilization of lysosomal cholesterol by virtue of the START domain's role in cholesterol transport. |
| MN blood group affects response of serum LDL cholesterol level to a low fat diet Birley, A. J., R. MacLennan, et al. (1997), Clin Genet 51(5): 291-5. Abstract: Previous studies found that MZ twin pairs who are blood group NN have greater intrapair variability in plasma lipid levels than those who are MM or MN. This led to the prediction that the response of plasma lipid levels to a low fat diet would depend on MN blood group, the greatest response being in those who are NN. The present study was based upon 254 patients who took part in the Australian Polyp Prevention Project. This was a 2 x 2 x 2 randomised factorial design based upon the presence or absence of the three factors: a dietary fibre supplement, a beta-carotene supplement and reduced intake of dietary fat. The lowering of plasma, low density lipoprotein (LDL) cholesterol, in response to a low fat diet was greatest in those who were NN and least in MN heterozygotes. Overall, a reduction in LDL level was observed in the 47% of the APPP population who were on a low fat diet and who were homozygous MM or NN. The result was consistent with a balanced polymorphism at or near the GLYA locus on chromosome 4 that influences the sensitivity of plasma lipid levels to dietary fluctuations in fat intake. |
| Mobilisation of tissue cholesterol by apheresis Thompson, G. R. (1990), Prog Clin Biol Res 337: 183-7. |
| Mobilization of late-endosomal cholesterol is inhibited by Rab guanine nucleotide dissociation inhibitor Holtta-Vuori, M., J. Maatta, et al. (2000), Curr Biol 10(2): 95-8. Abstract: Cholesterol entering cells in low-density lipoproteins (LDL) via receptor-mediated endocytosis is transported to organelles of the late endocytic pathway for degradation of the lipoprotein particles. The fate of the free cholesterol released remains poorly understood, however. Recent observations suggest that late-endosomal cholesterol sequestration is regulated by the dynamics of lysobisphosphatidic acid (LBPA)-rich membranes 1. Genetic studies have pinpointed a protein, Niemann-Pick C-1 (NPC-1), that is required for the mobilization of late-endosomal/lysosomal cholesterol by an unknown mechanism 2. Here, we report the removal of accumulated cholesterol by overexpression of the NPC-1 protein in NPC-1-deficient fibroblasts from patients with Niemann-Pick disease, and in normal fibroblasts upon release of a progesterone-induced block of cholesterol transport. We show that late-endosomal/lysosomal cholesterol mobilization is specifically inhibited by microinjection of Rab GDP-dissociation inhibitor (Rab-GDI). Moreover, clearance of the cholesterol deposits by NPC-1 in patients' fibroblasts is accompanied by the redistribution of LBPA and of a lysosomal hydrolase that utilizes the mannose-6-phosphate receptor. Our results reveal, for the first time, the involvement of a specific molecular component of the membrane-trafficking machinery in cholesterol transport and the coupling of late-endosomal cholesterol egress to the trafficking of other lipid and protein cargo. |
| Model for a one-step plasma treatment device: feasibility of cholesterol removal Brown, C. W., K. A. Solen, et al. (1997), Asaio J 43(6): 884-9. Abstract: A self-contained plasmapheresis device based on Starling flow has been proposed. A computer model was developed to describe the device performance, and a device using conventional cellulose tri-acetate (CTA) fibers was modeled. Predicted pressure drops and ultrafiltration flow agreed well with measurements using bovine blood in prototype devices made with CTA fibers. The model predicted the expected Starling flow and predicted the observed high hematocrit region near the fiber wall and a layer of packed red cells on the wall. Typically, 15% of the ultrafiltration flow occurred in the first 2-3% of the fiber length where no packed cell layer was present. The entrance header was predicted to cause lower blood pressures in the peripheral fibers, producing a net plasma migration from the central to the peripheral fibers. As an example application for this device, the computer model was used to assess the feasibility of reducing LDL-cholesterol in patients. The use of sequential 1 hour treatments by a modified device was predicted to reduce the cholesterol in a standard man from 200 mg% to 150 mg% in less than 3 hours. |
| Modeling cholesterol in humans: update and dealing with the problem of exchange in vivo using the blood cell-lipoprotein paradigm Schwartz, C. C., J. M. VandenBroek, et al. (2003), Adv Exp Med Biol 537: 207-19. |
| Models for risk of low cholesterol Hannan, P. J. (1993), J Clin Epidemiol 46(2): 203-4. |
| Models for the longitudinal genetic analysis of same-age twins: application to HDL cholesterol Nance, W. E., J. Bodurtha, et al. (1998), Twin Res 1(1): 3-8. Abstract: Models are presented for the analysis of longitudinal data from same-age twins which permit the exploration of a remarkably diverse array of alternative explanations for continuity and change during development. Data of this type permit the detection of new sources of genetic or environmental covariation during development that are not expressed at earlier ages and, because they include the effects of age-specific genes, the resulting heritability estimates are more reliable than those obtained from relatives who differ in age. The proposed models were applied to measurements of HDL cholesterol obtained on 81 pairs of monozygotic (MZ) twins and 69 dizygotic (DZ) pairs at 11, 12.5 and 14 years of age. All three MZ co-twin correlations were substantially higher than the self correlations across occasions, suggesting that new sources of genetic or environmental covariation must be expressed during early adolescence. This interpretation was confirmed by analysis of the full covariance matrices which showed that only models which assumed the expression of new or age-specific genes could explain the observed pattern of covariation. Because they include the effects of age-specific genes, the resulting heritabilities (0.80-0.83) were substantially higher than many previous estimates. |
| Models of effects of low blood cholesterol on the public health. Implications for practice and policy Jacobs, D. R., Jr. and H. Blackburn (1993), Circulation 87(3): 1033-6. |
| Moderate alcohol consumption increases cholesterol efflux mediated by ABCA1 Beulens, J. W., A. Sierksma, et al. (2004), J Lipid Res 45(9): 1716-23. Abstract: Moderate alcohol consumption increases HDL cholesterol, which is involved in reverse cholesterol transport (RCT). The aim of this study was to investigate the effect of moderate alcohol consumption on cholesterol efflux, using J774 mouse macrophages and Fu5AH cells, and on other parameters in the RCT pathway. Twenty-three healthy men (45-65 years) participated in a randomized, partially diet-controlled, crossover trial. They consumed four glasses of whisky (40 g of alcohol) or water daily for 17 days. After 17 days of whisky consumption, serum capacity to induce ABCA1-dependent cholesterol efflux from J774 mouse macrophages was increased by 17.5% (P = 0.027) compared with water consumption. Plasma capacity to induce cholesterol efflux from Fu5AH cells increased by 4.6% (P = 0.002). Prebeta-HDL, apolipoprotein A-I (apoA-I), and lipoprotein A-I:A-II also increased by 31.6, 6.2, and 5.7% (P < 0.05), respectively, after whisky consumption compared with water consumption. Changes of cAMP-stimulated cholesterol efflux correlated (r = 0.65, P < 0.05) with changes of apoA-I but not with changes of prebeta-HDL (r = 0.30, P = 0.18). Cholesterol efflux capacities from serum of lean men were higher than those from overweight men. In conclusion, this study shows that moderate alcohol consumption increases the capacity of serum to induce cholesterol efflux from J774 mouse macrophages, which may be mediated by ABCA1. |
| Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease Brown, B. G., J. Bardsley, et al. (1997), Am J Cardiol 80(2): 111-5. Abstract: The efficacy, safety, and tolerability of a moderate dose, 3-drug lipid-lowering regimen were evaluated among 29 male patients with hyperlipidemia and coronary artery disease. In an initial 12-month phase, regular niacin, 500 mg qid, lovastatin, 20 mg bid, and colestipol, 10 g/bid, were given with dose adjustment for lipid targets and side effects. This was followed by 2 random sequence crossover phases (8 months each) alternating regular niacin with a polygel controlled-release formulation of niacin for use in this regimen. Lipid, lipoprotein, apoprotein, and clinical chemistry determinations were obtained at baseline, during the initial phase, at the 2 crossover phases, and at 6 weeks after therapy. A final questionnaire queried specific side effects and overall preferences. Low-/high-density lipoprotein (LDL/HDL) changed from means of 215/46 mg/dl at baseline, to 94/59 mg/dl after run-in, to 85/52 mg/dl after 8 months of controlled-release niacin, and to 98/56 mg/dl after 8 months of regular niacin (regular niacin vs controlled-release niacin, p <0.005/<0.05). The target of LDL < or = 100 mg/dl was achieved at 8 months by 83% of these patients with controlled-release niacin and by 52% with regular niacin (p <0.01). Compliance was 95% with controlled-release niacin versus 85% with regular niacin (p <0.001). The controlled-release niacin and regular niacin regimens did not differ in terms of uric acid, glucose, insulin, or asparate aminotransferase levels. Overall, 21% of patients called the 3 drugs "very easy" and 72% "fairly easy" to take. The controlled-release niacin-containing regimen was preferred by 21 patients and the regular niacin by 4. In conclusion, these regimens achieve striking lipid changes among hyperlipidemic patients. Controlled release is the preferred niacin preparation in terms of LDL reduction, compliance, patient preference, and achieving the National Cholesterol Education Program guideline of LDL < or = 100 mg/dl. The 2 niacin preparations did not differ in evidence of toxicity. |
| Modification of enzymatic method of cholesterol determination Leszczynska, J. (1999), Rocz Panstw Zakl Hig 50(4): 421-6. Abstract: Fluorimetric substrates for peroxidase activity determining were described in this work so that to establish cholesterol concentration by enzymatic method. p-hydroxyphenyloacetate acid was used, as the most favourable, so that to determine cholesterol content in meat products. Using of this compound enables to diminish cholesterol determining limit more than 10-times. Obtained results of cholesterol content are convergent with results obtained by the other authors. |
| Modification of high-density lipoprotein cholesterol in the management of cardiovascular risk Koeller, J. and R. L. Talbert (2002), Pharmacotherapy 22(10): 1266-77. Abstract: Although several clinical trials clearly demonstrate a decrease in mortality and morbidity rates for various patient populations with cardiovascular disease, this disease continues to be the leading cause of death in the United States. Based on various practice surveys and descriptive reports, clinicians apparently are not identifying patients at risk or not treating them to established goals set by national guidelines. Most evidence, including the updated National Cholesterol Education Program Adult Treatment Panel III guidelines, support low-density lipoprotein cholesterol (LDL) as the principal target for intervention. The guidelines also emphasize that a low level of high-density lipoprotein cholesterol (HDL) alone or in association with hypertriglyceridemia increases the risk of cardiovascular disease; also, epidemiologic data taken as a whole signify that a 1% decrease in HDL levels is associated with a 2-3% increase in risk of coronary heart disease. Low HDL levels occur more frequently than once thought, especially in selected populations such as patients with type 2 diabetes and men. Therapeutic lifestyle changes should be implemented first for any lipid disorder. In patients for whom this approach is not adequate, LDL levels need to be lowered to goals based on risk assessment. In addition, low HDL levels and/or hypertriglyceridemia should be managed with a niacin or fibrate product. However, increases in HDL levels and reductions in triglyceride levels are modest with fibrates compared with the dose-related changes seen with niacin products. Reformulation of niacin into an extended-release form minimizes common adverse effects seen with crystalline or sustained-release niacin, and the beneficial effects on the lipid profile are maintained. |
| Modification of insulin, glucose and cholesterol levels in nonobese women undergoing liposuction: is liposuction metabolically safe? Robles-Cervantes, J. A., S. Yanez-Diaz, et al. (2004), Ann Plast Surg 52(1): 64-7. Abstract: An open autocontrolled clinical study was performed on 15 healthy nonobese women who underwent liposuction to establish how metabolic profiles are modified in the short-term postsurgical period. Preoperative glucose, insulin, and cholesterol levels were determined. Also, impedancometry was used to determinate body composition. After 3 postoperative weeks, the levels and determinations were again tested. The results demonstrated a significant difference in glucose, cholesterol, insulin secretion, and adiposity, but insulin levels, glucose-insulin relationship, and insulin sensitivity remained unaltered. From the results of this study, we consider liposuction to be a safe surgical procedure from a metabolic point of view because it improves the levels of cholesterol, glucose, and insulin secretion and at the same time decreases adiposity. Therefore, in the short term, liposuction can modify important markers for the development of type II diabetes mellitus and cardiovascular disease. |
| Modification of lipid composition of neuroblastoma C1300 N18 cells with liposomes alters the cholesterol content Gulaya, N. M., G. L. Volkov, et al. (1990), Neuroscience 34(3): 785-92. Abstract: Cell incubation with lecithin-cholesterol liposomes (1:1 mol/mol) caused enhancement of the cholesterol content. The level of cholesterol esters of total and phospholipid unsaturated fatty acids increased in cholesterol enriched cells. Simultaneously the amount of saturated fatty acids decreased and lysophosphatidylcholine appeared in the cells. On the contrary, cell incubation with lecithin liposomes resulted in cholesterol depletion. This effect was accompanied by a decrease of cholesterol esters, of total and phospholipid unsaturated fatty acids. The content of saturated fatty acids was raised in cells with reduced amount of cholesterol. The quantity of N-acylphosphatidylethanolamine and N-acylethanolamine, lipids newly found in neuroblastoma cells, also changed in cells with modified content of cholesterol. The physiological role of cell response to the changes of cholesterol level is discussed. |
| Modification of membrane cholesterol level affects expression and clustering of class I HLA molecules at the surface of JY human lymphoblasts Bodnar, A., A. Jenei, et al. (1996), Immunol Lett 54(2-3): 221-6. Abstract: Recently we have found that class I HLA molecules, key elements of the antigen presentation system for CD8 + effector cells, show a clustered lateral distribution (homoassociation) at the surface of activated human T- and B-lymphocytes as well as virus-transformed T- and B-lymphoblasts, in contrast to a disperse distribution on resting human PBLs (Matk6 et al. (1994) J. Immunol. 152, 3353; Bene et al. (1994) Eur. J. Immunol. 24, 2115). Expression of beta2m-free HLA heavy chains and exogenous beta2m have been shown as potential regulation factors of HLA-I clustering, which in turn may affect cytotoxic activity of CD8+ effector cells. Here we report a study on the effect of plasma membrane-modification (by exogenous cholesterol and phosphatidylcholine) on the expression of free HLA heavy chains and beta2m-bound HLA-I molecules on JY human B-lymphoblasts. The modulating effect of these two treatments on the lipid fluidity of cells was demonstrated by fluorescence anisotropy of DPH lipid probe. The lateral clustering (association) of HLA-I molecules was detected by flow cytometric fluorescence resonance energy transfer (FCET) and digital imaging microscopic photobleaching energy transfer (pbFRET) methods, using flourescein-isothiocyanate (FITC) (donor)- and tetramethyl-rhodamine-isothiocyanate (TRITC) (acceptor)-labeled W6/32 or KE2 antibodies directed against intact HLA-I molecules. Cholesterol enrichment of the plasma membrane increased membrane fluidity and reduced the expression of heavy- and light-chain determinants of HLA-I molecules and free heavy chains (FHCs). This was accompanied with a higher degree of HLA-I clustering as shown by the enhanced intermolecular energy transfer efficiency. In contrast, cholesterol depletion resulted in membrane fluidization and increased expression of HLA-I epitopes. Our results suggest that both cholesterol level and lipid structure/fluidity of the plasma membrane in lymphoblastoid cells may also potentially regulate lateral organization and consequently the presentation efficiency of HLA-I molecules. |
| Modification of radiation sensitivity of lymphocytes of the rat thymus gland using cholesterol-enriched autoliposomes Posokhov, V. S., O. A. Rozenberg, et al. (1992), Biull Eksp Biol Med 113(2): 136-8. Abstract: The influence of thymocyte enrichment with cholesterol on radiosensitivity of these cells has been studied. The enrichment was performed using autoliposomes. It was found that in the modified cells the processes of lipid peroxidation, enzymatic degradation of chromatin and apoptosis are inhibited. |
| Modification of the amount of cholesterol in hepatic steatosis induced in susceptible and resistant mice infected with MHV3: a biochemical and ultrastructural study Bingen, A., J. P. Martin, et al. (1992), Hepatology 15(6): 1137-46. Abstract: A mouse hepatitis virus-3 strain subcultured in our laboratory is a unique experimental model in which to study virus-induced liver steatosis. This strain produces massive lipid deposition not only in sensitive adult BALB/c mice but also (though less extensive) in virus-resistant adult A/J mice. Biochemical determinations have shown that this steatosis is characterized by an increased amount of neutral lipids (sterols and triglycerides) in infected livers of BALB/c mice and by a smaller increase in those of A/J mice. However, the relative percentage of cholesterol and triglycerides is similar in both strains. Liver phospholipid content was significantly decreased in both strains of mice. To discriminate between cytoplasmic and membrane cholesterol content in different types of liver cells, an ultrastructural study was performed with filipin, a specific cholesterol marker. This study shows on one hand an important increase in the cholesterol in the hepatocytes of BALB/c mice and a smaller increase in those of A/J mice, in agreement with biochemical data. However, marked cholesterol decrease and abnormal cholesterol distribution were observed in the endothelial liver cells of infected BALB/c mice. This decreased cholesterol content probably led to higher fluidity of these membranes, which could be related to the important drop in the number of endothelial cell fenestrae observed after mouse hepatitis virus-3 infection. Because in A/J infected mice neither a decrease in the amount and distribution of cholesterol nor decreased fenestration were observed in endothelial liver cells, these findings could be correlated with the resistance of these mice to the infection. |
| Modification of the cholesterol efflux properties of human serum by enrichment with phospholipid Jian, B., M. de la Llera-Moya, et al. (1997), J Lipid Res 38(4): 734-44. Abstract: To investigate the importance of phospholipid in promoting cholesterol efflux from cells, phospholipid multilamellar vesicles were incubated with normal human serum and the efflux ability of these lipid-modified sera was tested. When incubated under appropriate conditions, both dimyristoylphosphatidylcholine (DMPC) and bovine brain sphingomyelin (BBSM) were shown to combine with components of human serum to form new protein:lipid complexes and to markedly enhance the ability of serum to promote efflux of cholesterol from Fu5AH cells. In particular, the high density lipoprotein (HDL) particles were altered in their composition and electrophoretic properties and the alpha-migrating species, which were reactive with antibodies to apo-A-I, were converted to larger, pre-beta-migrating particles, similar in electrophoretic properties to pre beta(2)-HDL. DMPC, but not BBSM, also generated particles with mobility similar to pre beta(2)-HDL; These species were demonstrably different from the discoidal complexes formed by reaction of DMPC with purified apoA-I. However, no change in cholesterol efflux potential was observed when serum was mixed with phospholipids that failed to interact or when cells were incubated with phospholipid multilamellar vesicles alone. To further identify the components of serum that become altered in their efflux potential after reaction with phospholipid, isolated lipoprotein fractions were incubated with DMPC or BBSM and it was found that only interaction with HDL caused enhancement of cholesterol efflux. In summary, cholesterol removal from the Fu5AH cells by serum can be promoted by adding phospholipid under conditions where new HDL-like complexes can be formed between the phospholipid and serum components, most notably apolipoprotein A-I. |
| Modification of the dextran-Mg2+ high-density lipoprotein cholesterol precipitation method for use with previously frozen plasma McNamara, J. R., C. Huang, et al. (1994), Clin Chem 40(2): 233-9. Abstract: Although dextran-Mg2+ precipitation produces accurate and precise results for high-density lipoprotein (HDL) cholesterol in fresh plasma and serum, precipitation of frozen specimens with triglycerides > 2.26 mmol/L (> 200 mg/dL) is difficult. We developed a modification that dilutes thawed samples by 35% and increases dextran-Mg2+ reagent to 15% of sample volume. Standard precipitations were performed on 62 fresh EDTA-treated plasma specimens; supernatant solutions were analyzed fresh and after freezing. Standard and modified methods were also performed on thawed, paired plasmas. In specimens with triglycerides < or = 2.26 mmol/L, HDL cholesterol results for all methods were similar. For triglycerides > 2.26 mmol/L, however, bias and precision were significantly affected by freezing, and 38.5% of samples with standard precipitation required additional procedures to produce clear supernatant solutions. HDL cholesterol concentrations for thawed samples with standard precipitation were significantly greater than for fresh samples (P < 0.02), but those for the modified method were not different from fresh samples, and only one specimen required additional steps to produce a clear supernate. |