| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Contribution of cholesterol 7alpha-hydroxylase to the regulation of lipoprotein metabolism Cohen, J. C. (1999), Curr Opin Lipidol 10(4): 303-7. Abstract: Clinical studies have clearly established a relationship between bile acid synthesis and plasma LDL-cholesterol concentrations. Interruption of the enterohepatic circulation of bile acids leads to increased bile acid synthesis and a reduction in plasma LDL-cholesterol concentrations. New studies indicate that genetic variation in cholesterol 7alpha-hydroxylase activity accounts for a significant fraction of the inter-individual variation in plasma LDL-cholesterol concentrations in the general population, and a specific CYP7A1 allele associated with increased plasma LDL-cholesterol concentrations has been identified. Studies in which cholesterol 7alpha-hydroxylase was transiently overexpressed in hamsters and mice indicate that direct manipulation of cholesterol 7alpha-hydroxylase leads to changes in plasma LDL-cholesterol concentrations. Interestingly, targeted inactivation of the gene encoding cholesterol 7alpha-hydroxylase does not lead to increased plasma LDL-cholesterol concentrations in mice. |
| Contribution of cholesterol and phospholipids to inhibitory effect of dimethyl-beta-cyclodextrin on efflux function of P-glycoprotein and multidrug resistance-associated protein 2 in vinblastine-resistant Caco-2 cell monolayers Arima, H., K. Yunomae, et al. (2004), Pharm Res 21(4): 625-34. Abstract: PURPOSE: The purpose of this study is to reveal the contribution of membrane components to the inhibitory effect of 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD) on P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) function in vinblastine-resistant Caco-2 (Caco-2R) cell monolayers. METHODS: The transport of rhodamine-123 and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) was studied in Caco-2R cell monolayers. P-gp and MRP2 residing in the monolayers and releasing in cell supernatants were detected by Western blotting. The mRNA levels of MDR1 and MRP2 were detected by reverse transcription-polymerase chain reaction (RT-PCR) method. Cholesterol, phospholipids, and proteins were mainly determined by each assay kit. RESULTS: Of various beta-cyclodextrin derivatives (beta-CyDs), DM-beta-CyD most significantly impaired the efflux function of P-gp and MRP2 without changing cell viability and membrane integrity. The treatment with CyDs did not change the mRNA levels of MDR1 and MRP2. DM-beta-CyD lowered cholesterol content and P-gp level in caveolar membranes. In addition, DM-beta-CyD released not only cholesterol and phospholipids but also proteins including P-gp and MRP2 from apical membranes of the monolayers. CONCLUSIONS: DM-beta-CyD may impair P-gp and MRP2 function in Caco-2R cell monolayers, probably, at least in part, through the release of these transporters from the apical membranes of monolayers, and the exertion of the inhibitory effect of DM-beta-CyD may require the extraction of not only cholesterol but also phospholipids from the monolayers. |
| Contribution of cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase to HDL size distribution Huesca-Gomez, C., E. Carreon-Torres, et al. (2004), Endocr Res 30(3): 403-15. Abstract: High-density lipoproteins (HDL) includes a heterogeneous class of lipoproteins grouped into various subclasses that seem to have different antiatherogenic function. Cholesteryl ester transfer protein (CETP) and lecithin cholesterol acyltransferase (LCAT) play an active role in HDL remodeling. This study was designed to define the role of CETP and LCAT activities on HDL-cholesterol (HDL-C) plasma levels and HDL size distribution, as determined by nondenaturating polyacrylamide gradient gel electrophoresis in 47 clinically healthy Mexican individuals without personal and family history of coronary heart disease. Surprisingly, plasma activities of CETP (29+/-4.1% of transfer) and LCAT (4.8+/-2.2% of esterification) did not correlate either with HDL-C plasma levels or with any other lipid parameter, indicating the poor contribution of these proteins to the lipid profile. The CETP activity showed a negative correlation with small HDL3b (r = -0476, P < 0.05), whereas LCAT was positively associated with this HDL subclass (r = 0.466, P < 0.05). The LCAT showed a negative correlation with large HDL2a (r = - 0.674, P < 0.005). Nevertheless, when the LCAT/CETP ratio was calculated, we observed that the higher the ratio, the greater the relative proportion of small HDL3b (r = 0.551, P < 0.05) and HDL3c (r = 0.477, P < 0.05). These results suggest that the balance of LCAT and CETP activities have a great impact in the plasma HDL size distribution. |
| Contribution of dietary lipid change to falling serum cholesterol levels between 1980 to 1982 and 1985 to 1987 in an urban population. The Minnesota Heart Survey Graves, K. L., P. G. McGovern, et al. (1993), Ann Epidemiol 3(6): 605-13. Abstract: We assessed dietary intake and serum total cholesterol trends during the 1980s, in the Minneapolis-St. Paul (Twin Cities) metropolitan area. Twin Cities residents 25 to 74 years old participated in independent, cross-sectional, population-based surveys of risk factors for cardiovascular disease in 1980 to 1982 (n = 1611) and 1985 to 1987 (n = 2231). Age-adjusted total energy intake was similar in 1980 to 1982 and 1985 to 1987: 2528 kcal (10.6 MJ) versus 2574 kcal (10.8 MJ) for men and 1683 kcal (7.1 MJ) versus 1689 kcal (7.1 MJ) for women. However, significant changes were observed in macronutrient intake. The percent of energy from total fat intake decreased from 39.3 to 38.1% in men and 38.9 to 36.6% in women (both P < 0.01). The composition of fat consumed changed, such that the Keys score, an index of dietary fat and cholesterol, decreased by 3.3 units in both sexes (both P < 0.01). The predicted changes in serum total cholesterol (Keys score) were generally consistent with observed declines of 5.4 mg/dL (0.1 mmol/L) in men and 5.8 mg/dL (0.15 mmol/L) in women during this time period. These data suggest that members of this community are on average modifying their fat consumption and that these dietary changes are resulting in more favorable serum total cholesterol levels. |
| Contribution of hydrogen bonding to lipid-lipid interactions in membranes and the role of lipid order: effects of cholesterol, increased phospholipid unsaturation, and ethanol Slater, S. J., C. Ho, et al. (1993), Biochemistry 32(14): 3714-21. Abstract: It is proposed that increased phospholipid unsaturation in membranes and perturbation by agents such as ethanol weaken interlipid hydrogen bonding involving water and that the process is independent of effects on lipid order. To investigate this, the rates of phospholipid desorption, as a measure of the strength of interlipid interactions, from "donor" lipid vesicles was determined. This was accomplished using (7-nitrobenzo-2-oxa-1,3-diazole-4-yl)aminohexanoate (C6-NBD) labeled phospholipids, the rate of desorption being followed from changes in fluorescence with time. The rates of desorption of the NBD-phospholipids from phosphatidylcholine (PC) donor vesicles was in the order phosphatidylcholine (PC) > phosphatidylserine (PS) > phosphatidylethanolamine (PE), the slower rates in the PS and PE reflecting direct interlipid hydrogen bonding. For PC, the interlipid hydrogen bonding was restricted to the "hydration layer", the network of hydrogen-bonded water molecules extending between phospholipid head groups. The rate of C6-NBD-PC desorption was elevated with higher levels of donor PC sn-2 unsaturation, due the increased head group spacing weakening the lipid-lipid interactions that occur via the hydration layer. Ethanol also increased the rate of NBD-phospholipid desorption from donor PC vesicles in the order PC > PS > PE, showing that PC interactions, here limited to the weaker hydrogen-bonded water molecule network, were more susceptible compared to stronger, direct interlipid hydrogen bonds involving PE and PS. The relative magnitude of the ethanol-induced increase in the desorption rate was amplified with higher levels of donor lipid sn-2 unsaturation. Cholesterol had little effect on the rate of phospholipid desorption.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Contribution of individual tryptophan residues to the structure and activity of theta-toxin (perfringolysin O), a cholesterol-binding cytolysin Sekino-Suzuki, N., M. Nakamura, et al. (1996), Eur J Biochem 241(3): 941-7. Abstract: theta-Toxin (perfringolysin O), secreted by Clostridium perfringens, shares with other known thiol-activated toxins a conserved undecapeptide, ECTGLAWEWWR, located in the C-terminal region of the protein and containing the unique cysteine of the molecule. Single and double amino acid substitutions were created in the theta-toxin molecule to investigate the role of individual tryptophan residues in the lytic activity of theta-toxin. Wild-type and mutant theta-toxins were overproduced in Escherichia coli by means of a T7 RNA polymerase/promoter system and purified. The relative hemolytic activities of four mutant toxins, each with a Trp to Phe substitution outside the common Cys-containing region, were more than 60% that of wild-type theta-toxin. In contrast, mutant toxins with Phe replacements within the Cys-containing region (at Trp436, Trp438 or Trp439) showed significantly reduced hemolytic and erythrocyte-membrane-binding activities. The largest reduction in binding affinity, more than 100-fold, was observed for Trp438 mutant toxins. However, the mutants retain binding specificity for cholesterol and the ability to form arc-shaped and ring-shaped structures on membranes. These results indicate that the low hemolytic activities of these mutant toxins can be ascribed, at least in part, to reduced binding activities. With respect to protease susceptibility and far-ultraviolet circular-dichroism spectra, only the W436-->F mutant toxin, showed any considerable difference from wild-type toxin in secondary or higher-order structures, indicating that Trp436 is essential for maintenance of toxin structure. |
| Contribution of membrane cholesterol to outer hair cell lateral wall stiffness Nguyen, T. V. and W. E. Brownell (1998), Otolaryngol Head Neck Surg 119(1): 14-20. Abstract: The outer hair cell can be divided into three domains: the apex, the base, and the lateral wall. With the use of filipin, a polyene fluorescent antibiotic that binds to cholesterol, we found under fluorescence microscopy that the lateral wall membranes were less intensely stained than the apical and basal membranes. This difference in filipin fluorescence between the lateral walls and the ends diminished when cells were incubated in water-soluble cholesterol before staining, suggesting that exogenous cholesterol enters the lateral wall. Under confocal microscopy, we studied the incorporation pattern of a fluorescent cholesterol analogue, NBD-cholesterol. NBD-cholesterol did not stain the apical membranes whereas it intensely labeled the lateral wall. The micropipette aspiration technique was used to assess the effect of cholesterol on lateral wall stiffness. The lateral wall stiffness parameter of cells treated with water-soluble cholesterol (n = 23) was significantly higher than that of controls (n = 27): 0.76+/-0.24 (mean +/- SD) versus 0.46+/-0.10 (Student's t-test, p < 0.001). In conclusion, cholesterol has different distributions among outer hair cell membranes, and when water-soluble cholesterol is incorporated into the cells, the outer hair cell lateral wall stiffness parameter increases. |
| Contribution of newly synthesized cholesterol to rat plasma and bile determined by mass isotopomer distribution analysis: bile-salt flux promotes secretion of newly synthesized cholesterol into bile Bandsma, R. H., F. Stellaard, et al. (1998), Biochem J 329 (Pt 3): 699-703. Abstract: To quantify the contribution of newly synthesized cholesterol to total plasma and biliary cholesterol under physiological conditions, unrestrained rats were infused intravenously with 1-13Cacetate (0. 6mmol/h per kg) from 12:00 to 24:00 h, and fractional and absolute cholesterol-synthesis rates were determined by mass isotopomer distribution analysis (MIDA). As bile diversion leads to changes in cholesterol metabolism, rats were equipped with permanent catheters in the bile duct and duodenum, allowing sampling of small amounts of bile from an intact enterohepatic circulation. For comparison, rats with chronic bile diversion were also studied. Fractional synthesis of plasma cholesterol was 10.8+/-1.7% (mean+/-S.D.) after 12 h in rats with intact circulation. Fractional synthesis of biliary cholesterol was significantly higher than that of plasma cholesterol, i.e. 16.5+/-2.0% (P<0.05) after 12 h. In contrast, no differences between fractional synthesis of cholesterol in plasma and bile were found in bile-diverted animals (31.8+/-2.1 and 33.1+/-3.3% respectively after 12 h). The calculated absolute rate of cholesterol biosynthesis increased from 53+/-10 to 221+/-19 micromol/day per kg after bile diversion. A comparison of MIDA results with those obtained from balance studies indicated that MIDA does not assess total body synthesis in rats, presumably because of incomplete equilibration of newly synthesized molecules with cholesterol in the plasma compartment. These studies demonstrate that the contribution of newly synthesized cholesterol to biliary cholesterol is higher than to plasma cholesterol under physiological conditions, probably reflecting bile-salt-induced secretion of newly formed cholesterol by the periportal hepatocytes. |
| Contribution of postprandial lipemia to the dietary fat-mediated changes in endogenous lipoprotein-cholesterol concentrations in humans Chung, B. H., B. H. Cho, et al. (2004), Am J Clin Nutr 80(5): 1145-58. Abstract: BACKGROUND: Dietary fats alter LDL and HDL cholesterol while serving as precursors of postprandial triacylglycerol-rich lipoproteins (TRLs). OBJECTIVE: We hypothesized that the saturated fatty acid (SFA)-mediated increase and the polyunsaturated fatty acid (PUFA)-mediated decrease in endogenous lipoprotein cholesterol are promoted by postprandial TRLs. DESIGN: We performed a 16-d crossover diet study to examine the effect of PUFA-rich ratio of PUFAs to SFAs (P:S) = 2.0 and SFA-rich (P:S = 0.25) diets on fasting and postprandial plasma lipid and lipoprotein-cholesterol concentrations in 16 normolipidemic subjects. RESULTS: Fasting plasma cholesterol decreased significantly after a PUFA-rich diet because of a decrease in LDL (-12.3%; P < 0.05) and HDL (-3.8%; NS), but did not change after an SFA-rich diet. The appearance of postprandial TRLs in plasma at 4 h was linked to a significant lowering of both LDL (-7.4%) and HDL (-4.8%) after a PUFA-rich diet; no such effect was observed after the SFA-rich diet. At 7 h, LDL and HDL cholesterol returned to near fasting concentrations without postprandial TRL accumulation after a PUFA-rich diet but with a significant postprandial TRL accumulation after an SFA-rich diet. Thus, the in vivo postprandial clearance of cholesterol in LDL+HDL was greater after a PUFA-rich diet than after an SFA-rich diet. The appearance of postprandial TRLs in plasma increased the cholesteryl ester transfer protein-mediated transfer of cholesteryl ester from LDL+HDL to TRLs in vitro without a significant influence from dietary fat. CONCLUSION: Dietary fat-mediated alterations in the rate of hepatic removal of postprandial TRLs, which carry cholesterol accepted from LDL+HDL via cholesteryl ester transfer protein in vivo, may contribute to the dietary fat-mediated change in endogenous lipoprotein cholesterol. |
| Contribution of specific foods to fat, fatty acids, and cholesterol in the development of a food frequency questionnaire in Koreans Kim, J., Y. J. Kim, et al. (2004), Asia Pac J Clin Nutr 13(3): 265-72. Abstract: The present study identified dietary sources of fat, fatty acids, and cholesterol in Koreans residing in and near Seoul. The study also identified foods to be included in a food frequency questionnaire (FFQ) by both contribution analysis (CA) and multiple regression analysis (MRA). Three-day dietary records were collected from 224 subjects (107 men and 117 women) aged 30 to 85 years. Pork was the main source of total fat and the largest contributor to saturated fatty acids (SFA) was beef. MRA identified animal food as the primary source of between-person variance for SFA. Arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid originated primarily from marine products. About a fourth of the total cholesterol intake was derived from chickens' eggs by CA, while chickens' eggs accounted for 46% of the cholesterol intake for between-person variance by MRA. With 10 food items, the FFQ could explain more than half of total intakes except for total fat and n-3 polyunsaturated fatty acids (PUFA), and at least 65% of between-person variances. The percentage coverage in the FFQ ranged from 61% for n-6 PUFA and linoleic acid and to 90% for arachidonic acid. The value of this FFQ is that it can estimate usual dietary food patterns and nutrient intake in Koreans for epidemiological studies. It can also potentially be used to study the relationship between specific diseases and nutrient intakes of interest. |
| Contribution of steroidogenic factor 1 to the regulation of cholesterol synthesis Mascaro, C., A. Nadal, et al. (2000), Biochem J 350 Pt 3: 785-90. Abstract: Steroidogenic factor 1 (SF-1) is an orphan member of the nuclear receptor family expressed in steroidogenic tissues, where it has an essential role in the regulation of the steroid hormone biosynthesis, adrenal and gonadal development and endocrine responses fundamental for reproduction. Here we show that SF-1 regulates the transcription of cytosolic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene, which is essential for the endogenous synthesis of cholesterol. We have identified an element located 365 bp upstream of the gene for cytosolic HMG-CoA synthase; SF-1 binds as a monomer to this element and confers SF-1 responsiveness to homologous and heterologous promoters. It has been shown that in tissues with a high demand for cholesterol to be used in steroid synthesis, there is a lack of correlation between the cholesterol levels and the activity of the limiting enzymes of the mevalonate pathway. In accord with those results, we observed that cholesterol synthesis from acetate and either cytosolic HMG-CoA mRNA expression or transcriptional activity were not changed in response to 25-hydroxycholesterol in the SF-1-expressing steroidogenic Leydig tumour MA-10 cells. Moreover, the overexpression of SF-1 in non-steroidogenic CV-1 cells renders them less sensitive to the regulatory effects of cholesterol. This observation led to the hypothesis that in steroidogenic tissues the expression of SF-1 permits high levels of endogenous synthesis of cholesterol irrespective of the intracellular levels of this metabolite. |
| Contribution of the cholesteryl ester transfer protein gene TaqIB polymorphism to the reduced plasma HDL-cholesterol levels found in abdominal obese men with the features of the insulin resistance syndrome Vohl, M. C., B. Lamarche, et al. (1999), Int J Obes Relat Metab Disord 23(9): 918-25. Abstract: OBJECTIVE: The aim of this study was to examine the relation between the CETP-TaqIB polymorphism and reduced plasma HDL-cholesterol levels commonly observed among men characterized by abdominal obesity and features of the insulin resistance syndrome. SUBJECTS: A total of 187 sedentary men, non-smokers and free from metabolic disorders were classified on the basis of their CETP-TaqIB genotype. RESULTS: Plasma HDL and HDL3-cholesterol concentrations as well as the CETP activity were significantly different between the three genotypes, B1B1 men having significantly lower HDL and HDL3-cholesterol levels and higher CETP activity than B2B2 homozygotes. A 2x3 ANOVA was used to determine the source of variation of plasma HDL and HDL2-cholesterol levels among the three genotypic groups of men divided on the basis of either a high (>/=27 kg/m2) or a low (<27 kg/m2) BMI, a high (>/=130 cm2) or a low (<130 cm2) accumulation of visceral adipose tissue assessed by computed tomography, or a low versus a high fasting plasma insulin concentration (using the median value as a cut-off point). The effect of the CETP genotype observed on plasma HDL-cholesterol concentrations was attenuated among men with features of the insulin resistance syndrome. It seems that the expected raising effect of the B2 allele on plasma HDL-cholesterol concentrations was blunted in the presence of a BMI>/=27 kg/m2, a high accumulation of visceral adipose tissue or hyperinsulinaemia. CONCLUSION: Our data indicate that the CETP gene TaqIB polymorphism influences plasma CETP activity on one hand and plasma HDL-cholesterol concentrations on the other hand among men. The association between the TaqIB polymorphism and plasma HDL-cholesterol concentrations is altered by the presence of abdominal obesity and some features of the insulin resistance syndrome. |
| Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha Venkateswaran, A., B. A. Laffitte, et al. (2000), Proc Natl Acad Sci U S A 97(22): 12097-102. Abstract: LXR alpha is a nuclear receptor that has previously been shown to regulate the metabolic conversion of cholesterol to bile acids. Here we define a role for this transcription factor in the control of cellular cholesterol efflux. We demonstrate that retroviral expression of LXR alpha in NIH 3T3 fibroblasts or RAW264.7 macrophages and/or treatment of these cells with oxysterol ligands of LXR results in 7- to 30-fold induction of the mRNA encoding the putative cholesterol/phospholipid transporter ATP-binding cassette (ABC)A1. In contrast, induction of ABCA1 mRNA in response to oxysterols is attenuated in cells that constitutively express dominant-negative forms of LXR alpha or LXR beta that lack the AF2 transcriptional activation domain. We further demonstrate that expression of LXR alpha in NIH 3T3 fibroblasts and/or treatment of these cells with oxysterols is sufficient to stimulate cholesterol efflux to extracellular apolipoprotein AI. The ability of oxysterol ligands of LXR to stimulate efflux is dramatically reduced in Tangier fibroblasts, which carry a loss of function mutation in the ABCA1 gene. Taken together, these results indicate that cellular cholesterol efflux is controlled, at least in part, at the level of transcription by a nuclear receptor-signaling pathway. They suggest a model in which activation of LXRs by oxysterols in response to cellular sterol loading leads to induction of the ABCA1 transporter and the stimulation of lipid efflux to extracellular acceptors. These findings have important implications for our understanding of mammalian cholesterol homeostasis and suggest new opportunities for pharmacological regulation of cellular lipid metabolism. |
| Control of cholesterol access to cytochrome P450scc in rat adrenal cells mediated by regulation of the steroidogenic acute regulatory protein Kim, Y. C., N. Ariyoshi, et al. (1997), Steroids 62(1): 10-20. Abstract: Cholesterol conversion to pregnenolone by cytochrome P450scc in steroidogenic cells, including those of the adrenal cortex, is determined by hormonal control of cholesterol availability. Intramitochondrial cholesterol movement to P450scc, which retains hormonal activation in isolated mitochondria, is apparently dependent on peripheral benzodiazepine receptor and the recently cloned steroidogenic acute regulatory (StAR) protein. In rat adrenal cells, StAR is formed as a 37-kDa precursor that is transferred to the mitochondrial inner membrane following phosphorylation by hormonally activated protein kinase A, and processed to multiple forms, some of which turn over very rapidly. In bovine cells, StAR undergoes three modifications forming a set of eight proteins seen in both glomerulosa and fasciculata cells. In the former, cyclic AMP and angiotensin II each decrease two forms and elevate six forms. Significantly, the major change seen after activation may not involve phosphorylation of StAR. Cholesterol transfer across mitochondrial membranes is also activated in isolated mitochondria by GTP and low concentrations of Ca2+, apparently prior to activation by StAR. Depletion of StAR by cycloheximide inhibits cholesterol transfer but is overcome by uptake of Ca2+ into the matrix. This activation of cellular cholesterol transport is sustained in adrenal cells permeabilized by Streptolysin O. In rat adrenal cells cAMP elevates 3.5- and 1.6-kb mRNA, hybridized by a 1.0-kb StAR cDNA. A 3.5-kb rat adrenal cDNA that encodes all except the 5' end of the longest StAR mRNA has been characterized. The corresponding gene sequence is distributed across seven exons. The shorter mRNA may arise from polyadenylation signals early in exon 7. However, the 3.5-kb mRNA comprises 80-90% of untreated rat adrenal StAR mRNA and may therefore provide the prime source for in vivo translation of StAR protein. |
| Control of cholesterol biosynthesis in Schwann cells Fu, Q., J. F. Goodrum, et al. (1998), J Neurochem 71(2): 549-55. Abstract: Cholesterol accounts for over one-fourth of total myelin lipids. We found that, during development of the rat sciatic nerve, expression of mRNA for hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, was up-regulated in parallel with mRNA for P0, the major structural protein of PNS myelin, and with ceramide galactosyltransferase (CGT), the rate-limiting enzyme in cerebroside biosynthesis. To help establish the nature of this coordinate regulation of myelin-related genes, we examined their steady-state mRNA levels in cultured primary Schwann cells. We also assayed synthesis of cholesterol and cerebroside to distinguish how much control of synthetic activity for these two myelin lipids involved mRNA levels for HMG-CoA reductase and CGT, and how much involved post-mRNA control mechanisms. Addition of forskolin to cells cultured in media supplemented with normal calf serum resulted in up-regulation of P0 and CGT mRNA expression and cerebroside synthesis, without corresponding increases in HMG-CoA reductase mRNA or cholesterol synthesis. Cholesterol synthesis increased approximately threefold in Schwann cells cultured with lipoprotein-deficient serum, without any increase in HMG-CoA reductase mRNA. Furthermore, addition of either serum lipoproteins or 25-hydroxycholesterol decreased cholesterol synthesis without altering HMG-CoA reductase mRNA levels. We conclude that, as in other tissues, cholesterol synthesis in Schwann cells is regulated primarily by intracellular sterol levels. Much of this regulation occurs at posttranscriptional levels. Thus, the in vivo coordinate up-regulation of HMG-CoA reductase gene expression in myelinating Schwann cells is secondary to intracellular depletion of cholesterol, as it is compartmentalized within the myelin. It is probably not due to coordinate control at the level of mRNA expression. |
| Control of cholesterol turnover in the mouse Dietschy, J. M. and S. D. Turley (2002), J Biol Chem 277(6): 3801-4. |
| Control of human sperm intracellular pH by cholesterol and its relationship to the response of the acrosome to progesterone Cross, N. L. and P. Razy-Faulkner (1997), Biol Reprod 56(5): 1169-74. Abstract: When incubated in vitro, human sperm gradually become capable of acrosome-reacting in response to the agonist progesterone. Loss of unesterified cholesterol is required for sperm to become responsive to progesterone, but how cholesterol regulates acrosomal responsiveness is unknown. These experiments tested the hypothesis that loss of sperm cholesterol leads to a rise in the intracellular pH (pH(i)) that makes the sperm responsive to progesterone. pH(i) was measured using BCECF (2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein) in freshly ejaculated sperm (T0 sperm) and in sperm incubated in vitro overnight (T24 sperm). During incubation, pH(i) increased from 6.94 +/- 0.03 to 7.08 +/- 0.01 (mean +/- SEM, n = 4, p < 0.01). Incubating sperm 24 h in medium supplemented with 1 microM cholesterol to prevent loss of sperm cholesterol suppressed the rise of pH(i) (T24C sperm, pH(i) = 6.96 +/- 0.03, n = 4, p = 0.64 compared to T0 sperm). To test whether their lower pH(i) prevents T24C sperm from reacting, we treated T24C sperm with the alkalinizing agents trimethylamine chloride (TMA) or NH4Cl. These agents did cause T24C sperm to respond to progesterone in a dose-dependent fashion, but they also caused a similar increase in the number of reacting T24 sperm. These agents probably do not reverse the inhibiting effects of high cholesterol but rather make responsive a subpopulation of sperm that is present regardless of the cholesterol content. NH4Cl and TMA did not make T0 sperm responsive to progesterone. The acidifying agent sodium propionate did not diminish the response of T24 sperm to progesterone. In summary, pH(i) increases during incubation in vitro in a cholesterol-dependent fashion. Elevated pH(i) alone is probably not sufficient to make sperm acrosomally responsive. |
| Control of lipid membrane stability by cholesterol content Raffy, S. and J. Teissie (1999), Biophys J 76(4): 2072-80. Abstract: Cholesterol has a concentration-dependent effect on membrane organization. It is able to control the membrane permeability by inducing conformational ordering of the lipid chains. A systematic investigation of lipid bilayer permeability is described in the present work. It takes advantage of the transmembrane potential difference modulation induced in vesicles when an external electric field is applied. The magnitude of this modulation is under the control of the membrane electrical permeability. When brought to a critical value by the external field, the membrane potential difference induces a new membrane organization. The membrane is then permeable and prone to solubilized membrane protein back-insertion. This is obtained for an external field strength, which depends on membrane native permeability. This approach was used to study the cholesterol effect on phosphatidylcholine bilayers. Studies have been performed with lipids in gel and in fluid states. When cholesterol is present, it does not affect electropermeabilization and electroinsertion in lipids in the fluid state. When lipids are in the gel state, cholesterol has a dose-dependent effect. When present at 6% (mol/mol), cholesterol prevents electropermeabilization and electroinsertion. When cholesterol is present at more than 12%, electropermeabilization and electroinsertion are obtained under milder field conditions. This is tentatively explained by a cholesterol-induced alteration of the hydrophobic barrier of the bilayer core. Our results indicate that lipid membrane permeability is affected by the cholesterol content. |
| Control of P-glycoprotein activity by membrane cholesterol amounts and their relation to multidrug resistance in human CEM leukemia cells Gayet, L., G. Dayan, et al. (2005), Biochemistry 44(11): 4499-509. Abstract: P-glycoprotein (P-gp) is the most well-known ATP-binding cassette (ABC) transporter involved in unidirectional substrate translocation across the membrane lipid bilayer, thereby causing the typical multidrug resistance (MDR) phenotype expressed in many cancers. We observed that in human CEM acute lymphoblastic leukemia cells expressing various degrees of chemoresistance and where P-gp was the sole MDR-related ABC transporter detected, the amount of esterified cholesterol increased linearly with the level of resistance to vinblastine while the amounts of total and free cholesterol increased in a nonlinear way. Membrane cholesterol controlled the ATPase activity of P-gp in a linear manner, whereas the P-gp-induced daunomycin efflux decreased nonlinearly with the depletion of membrane cholesterol. All these elements suggest that cholesterol controls both the ATPase and the drug efflux activities of P-gp. In addition, in CEM cell lines that expressed increasing levels of elevated chemoresistance, the amount of P-gp increases to a plateau value of 40% of the total membrane proteins and remained unvaried while the amount of membrane cholesterol increased with the elevation of the MDR level, strongly suggesting that cholesterol may be directly involved in the typical MDR phenotype. Finally, we showed that the decreased daunomycin efflux by P-gp due to the partial depletion of membrane cholesterol was responsible for the efficient chemosensitization of resistant CEM cells, which could be totally reversed after cholesterol repletion. |
| Control of plasma cholesterol-lowering action of probucol with various lipid carrier systems Takino, T., N. Koreeda, et al. (1998), Biol Pharm Bull 21(5): 492-7. Abstract: In order to explore the relationship between the pharmacokinetic properties and pharmacological actions of lipophilic drugs injected with lipid carrier systems, probucol was selected as a model drug with high lipophilicity, and the effect of disposition control on cholesterol-lowering activities was evaluated. Both large emulsion, with mean diameter of 280 nm, and long-circulating type small emulsion containing egg sphingomyelin with mean diameter of 100 nm, showed stable incorporation of probucol. The former produced rapid accumulation of probucol in the liver, while the latter demonstrated prolonged systemic circulation and gradual hepatic uptake. On the other hand, injection of a micellar solution with HCO-60 (polyoxyethylene hydrogenated castor oil) showed a rapid decrease in plasma concentration and a high hepatic uptake of probucol, similar to injections with serum, suggesting the rapid release of the drug from the micelles. However, probucol in a micellar solution showed higher cholesterol-lowering action than that in emulsion formulations. These results suggested that the pharmacological action of probucol in the liver might be affected by the uptake mode and sequential disposition in the organ, depending on the drug retention properties of the lipid carrier particles. |