| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Membrane cholesterol modulates serotonin transporter activity Scanlon, S. M., D. C. Williams, et al. (2001), Biochemistry 40(35): 10507-13. Abstract: The synaptic actions of the neurotransmitter serotonin are terminated by a selective high-affinity reuptake mediated by the serotonin transporter (SERT). To gain insight into the modulation of the functional properties of this integral membrane protein by cholesterol, a main component of the lipid bilayer, we stably expressed the rat SERT in human embryonic kidney 293 cells and, upon altering the cholesterol content of these cells by different means, analyzed SERT activity. Depletion of the level of membrane cholesterol by treatment with either the cholesterol chelating agent methyl-beta-cyclodextrin (MbetaCD), cholesterol oxidase, or the cholesterol-binding fluorochrome filipin resulted in a decrease in SERT activity due to both a loss of affinity of substrate and ligand binding and a concomitant reduction of the maximal transport rate. In cholesterol-depleted membranes, cholesterol levels could be restored to those found in untreated membranes by incubation of the membranes with an MbetaCD-cholesterol complex, which correlated with a reversal of the cholesterol depletion-mediated decrease in the level of high-affinity binding. This was not the case when other steroids, such as ergosterol, 5-cholestene, or pregnenolone, were substituted into cholesterol-depleted membranes. These results suggest that membrane cholesterol modulates the functional properties of the SERT by specific molecular interactions which are needed to stabilize the transporter in its optimally active form. |
| Membrane cholesterol oxidation inhibits ligand binding function of hippocampal serotonin(1A) receptors Pucadyil, T. J., S. Shrivastava, et al. (2005), Biochem Biophys Res Commun 331(2): 422-7. Abstract: We have monitored the ligand binding function of the bovine hippocampal 5-HT(1A) receptor following treatment of native membranes with cholesterol oxidase. Cholesterol oxidase is a water soluble enzyme that acts on the membrane interface to catalyze the conversion of cholesterol to cholestenone. Oxidation of membrane cholesterol significantly inhibits the specific binding of the agonist and antagonist to 5-HT(1A) receptors. Fluorescence polarization measurements of membrane probes incorporated at different locations in the membrane revealed no appreciable effect on membrane order due to the oxidation of cholesterol to cholestenone. These results therefore suggest that the ligand binding function of the 5-HT(1A) receptor is a cholesterol-dependent phenomenon that is not related to the ability of cholesterol to modulate membrane order. Importantly, these results represent the first report on the effect of a cholesterol-modifying agent on the ligand binding function of this important neurotransmitter receptor. |
| Membrane cholesterol regulates LFA-1 function and lipid raft heterogeneity Marwali, M. R., J. Rey-Ladino, et al. (2003), Blood 102(1): 215-22. Abstract: Many surface receptors and signaling molecules are thought to associate with unique membrane microdomains termed lipid rafts. We examined the involvement of lipid rafts in the activation of leukocyte function-associated antigen-1 (LFA-1). Depletion or sequestration of cholesterol with methyl-beta-cyclodextrin (MCD) or filipin, respectively, strongly inhibited LFA-1-mediated adhesion of T-cell lines and primary T cells. This inhibition was reversed by cholesterol reconstitution. LFA-1 on T-cell lines was detected in cold Triton X-100-insoluble lipid rafts, which were disrupted by MCD or filipin treatment. However, no LFA-1 on primary T cells was detected in lipid rafts isolated by the same procedures, and these rafts were resistant to cholesterol depletion or sequestration. Association of LFA-1 with lipid rafts of primary T cells could be detected only when they were isolated with another nonionic detergent, Brij 35. Upon treatment with MCD, LFA-1 in Brij 35-insoluble lipid rafts partially shifted to nonraft fractions. T-cell lines were found to have a high level of cholesterol and a low level of ganglioside GM1, a common marker for lipid rafts, whereas primary T cells have a much lower level of cholesterol and a very high amount of GM1. Cross-linking of LFA-1 on primary T cells induced cocapping of cholesterol but not GM1. These results suggest that lipid rafts of T cells are heterogenous, and LFA-1 associates with a subset of lipid rafts containing a high level of cholesterol. This association seems to regulate LFA-1 functions, possibly by facilitating LFA-1 clustering. |
| Membrane cholesterol regulates smooth muscle phasic contraction Babiychuk, E. B., R. D. Smith, et al. (2004), J Membr Biol 198(2): 95-101. Abstract: The regulation of contractile activity in smooth muscle cells involves rapid discrimination and processing of a multitude of simultaneous signals impinging on the membrane before an integrated functional response can be generated. The sarcolemma of smooth muscle cells is segregated into caveolar regions-largely identical with cholesterol-rich membrane rafts-and actin-attachment sites, localized in non-raft, glycerophospholipid regions. Here we demonstrate that selective extraction of cholesterol abolishes membrane segregation and disassembles caveolae. Simultaneous measurements of force and Ca2+i in rat ureters demonstrated that extraction of cholesterol resulted in inhibition of both force and intracellular Ca2+ signals. Considering the major structural reorganization of cholesterol-depleted sarcolemma, it is intriguing to note that decreased levels of membrane cholesterol are accompanied by a highly specific inhibition of phasic, but not tonic contractions. This implies that signalling cascades that ultimately lead to either phasic or tonic response may be spatially segregated in the plane of the sarcolemma. Replenishment of cholesterol restores normal contractile behavior. In addition, the tissue function is re-established by inhibiting the large-conductance K(+)-channel. Sucrose gradient ultracentrifugation in combination with Western blotting analysis demonstrates that its alpha-subunit is associated with detergent-resistant membranes, suggesting that the channel might be localized within the membrane rafts in vivo. These findings are important in understanding the complex signalling pathways in smooth muscle and conditions such as premature labor and hypertension. |
| Membrane cholesterol, lateral mobility, and the phosphatidylinositol 4,5-bisphosphate-dependent organization of cell actin Kwik, J., S. Boyle, et al. (2003), Proc Natl Acad Sci U S A 100(24): 13964-9. Abstract: Responses to cholesterol depletion are often taken as evidence of a role for lipid rafts in cell function. Here, we show that depletion of cell cholesterol has global effects on cell and plasma membrane architecture and function. The lateral mobility of membrane proteins is reduced when cell cholesterol is chronically or acutely depleted. The change in mobility is a consequence of the reorganization of the cell actin. Binding of a GFP-tagged pleckstrin homology domain specific for phosphatidylinositol 4,5-bisphosphate PI(4,5)P2 to the plasma membrane is reduced after cholesterol depletion. This result implies that the reorganization of cytoskeleton depends on the loss or redistribution of plasma membrane PI(4,5)P2. Consistent with this observation, agents that sequester plasma membrane PI(4,5)P2 mimic the effects of cholesterol depletion on actin organization and on lateral mobility. |
| Membrane cholesterol, protein phosphorylation, and lipid rafts Edidin, M. (2001), Sci STKE 2001(67): PE1. Abstract: The functions of cholesterol and membrane microdomains in transmembrane signaling remain controversial. Edidin discusses the questions surrounding lipid rafts, membrane microdomains that have been biochemically defined but are difficult to visualize in vivo. He also discusses whether experiments showing correlation of changes in plasma membrane cholesterol with differentiation and the formation of adherens junctions in endothelial cells are consistent with a model in which lipid rafts influence the regulation of these processes. |
| Membrane dynamics, cholesterol homeostasis, and Alzheimer's disease Chauhan, N. B. (2003), J Lipid Res 44(11): 2019-29. Abstract: Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid (A beta) plaques derived from the amyloidogenic processing; of a transmembrane protein called beta-amyloid precursor protein (APP). In addition to the known genetic/sporadic factors that promote the formation of A beta, the composition and structural dynamics of the membrane are also thought to play a significant role in the amyloidogenic processing of APP that promotes seeding of A beta. This minireview reinforces the roles played by membrane dynamics, membrane microdomains, and cholesterol homeostasis in relation to amyloidogenesis, and reviews current strategies of lowering cholesterol in treating AD. |
| Membrane fluidity and oxygen diffusion in cholesterol-enriched endothelial cells Dumas, D., V. Latger, et al. (1999), Clin Hemorheol Microcirc 21(3-4): 255-61. Abstract: In this study, we measured the influence of cholesterol rigidification on oxygen permeability in human endothelial cell monolayer membranes (ECs). Cholesterol-induced membrane rigidification was assessed at different membrane depths by a fluorescence polarization method with diphenyl-hexatriene (DPH) and 1-(4-trimethylamino)-6-phenylhexatriene (TMA-DPH). Fluorescence quenching by oxygen was probed in preferentially labelled membrane with pyrene butyric acid (PyC4) and pyrene dodecanoic acid (PyC12), as shown with a 3D fluorescence microscope (CellScan System). With both probes the experiments revealed a decrease in oxygen diffusion as the cholesterol concentration increased in the medium culture (from 3.42 microM to 17.11 microM). We showed that very low concentrations of cholesterol (about 1000 times below normal value, 6.2 mM) particularly decrease oxygen levels or diffusion rate in the middle region of the membrane. In conclusion, these findings prove in a direct manner that cholesterol significantly affect the endothelial barrier function and molecular oxygen transfer to underlying tissues. Risk factors (cholesterol) directly would contribute to tissue ischemia. |
| Membrane fluidity and oxygen diffusion in cholesterol-enriched erythrocyte membrane Dumas, D., S. Muller, et al. (1997), Arch Biochem Biophys 341(1): 34-9. Abstract: This work studied the effect of cholesteryl hemisuccinate incorporation on membrane fluidity and on the kinetics of oxygen diffusion at different depths in the erythrocyte membrane. Cholesterol concentration in the membrane was expressed as the cholesterol-protein ratio (C/Pt). The membrane fluidity, as assessed by a fluorescence polarization method with diphenyl-hexatriene and 1-(4-trimethylamino)-6-phenylhexa-1,3,5-triene, decreased as the C/Pt ratio increased. Time-resolved fluorescence spectroscopy of pyrene dodecanoic acid (PDA) under an increasing C/Pt ratio in the erythrocyte membrane revealed enhanced oxygen diffusion in the middle of the membrane bilayer (in which PDA was incorporated), which was not the case with pyrene butyric acid (PBA) incorporated in the internal part of the membrane surface. It has generally been accepted that increased membrane fluidity reduces the physical barrier to oxygen permeation. Such conflicting observations on oxygen permeation in the rigidified erythrocyte membrane could be due to variations in oxygen solubility (preferential partitioning) in different polarity microdomains (cholesterol and phospholipid partitions). |
| Membrane fluidity is related to the extent of glycation of proteins, but not to alterations in the cholesterol to phospholipid molar ratio in isolated platelet membranes from diabetic and control subjects Winocour, P. D., C. Watala, et al. (1992), Thromb Haemost 67(5): 567-71. Abstract: Platelets from diabetic subjects are hypersensitive to aggregating agents in vitro. Membrane fluidity modulates cell function and we previously reported reduced membrane fluidity associated with hypersensitivity to thrombin in intact platelets from diabetic subjects. Reduced membrane fluidity and hypersensitivity to agonists has also been reported in platelets from non-diabetic subjects whose platelets have an increased cholesterol/phospholipid molar ratio. Glycation of platelet membrane proteins is enhanced in diabetic subjects, and could contribute to the decreased membrane fluidity in these platelets. We examined the relation among fluidity, cholesterol/phospholipid molar ratio, and glycation of proteins in isolated platelet membranes from diabetic and control subjects. Seven poorly controlled diabetic subjects were compared with 7 age- and sex-matched control subjects. The mean steady-state fluorescence polarization value in 1,6-diphenyl-1,3,5-hexatriene-labeled isolated platelet membranes from diabetic subjects (0.184 +/- 0.004) was significantly greater than from control subjects (0.171 +/- 0.004, p less than 0.01); thus, fluidity in platelet membranes from diabetic subjects is decreased. Reduced fluidity in platelet membranes from diabetic subjects could not be attributed to changes in the cholesterol/phospholipid molar ratio. Total or very low density (VLDL), low density (LDL), or high density (HDL3) lipoprotein cholesterol concentration in plasma was not significantly different between groups, but the ratio of VLDL+LDL to HDL2 + HDL3 cholesterol was significantly greater in diabetic subjects (4.79 +/- 0.73) than in control subjects (2.54 +/- 0.30, p less than 0.02). Proteins were glycated significantly more extensively in platelet membranes from diabetic subjects (25.5 +/- 0.9 nmol glucose/mg protein) than those from control subjects (21.0 +/- 0.6 nmol glucose/mg protein, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) |
| Membrane interaction of calcium channel antagonists modulated by cholesterol. Implications for drug activity Mason, R. P. (1993), Biochem Pharmacol 45(11): 2173-83. Abstract: The interactions of lipophilic calcium channel antagonists with the membrane lipid bilayer are complex and highly dependent on membrane composition and structure. Variability in membrane lipid composition (e.g. cholesterol content, acyl chain saturation) can dramatically affect the membrane partitioning of calcium channel antagonists. The membrane binding properties of these drugs did not correlate with traditional measurements of drug lipophilicity, such as a simple hydrocarbon system (Table 2). These data indicate the need for directly measuring the binding of drug molecules to membranes in order to understand better certain pharmacological parameters, including bioavailability, under both normal and pathological conditions in which membrane composition is altered. The interaction of certain lipophilic amphipathic drugs with the membrane lipid bilayer may be an important component of their overall receptor binding mechanism. Specifically, the membrane bilayer may serve to concentrate and orient these drug molecules with respect to a hydrophobic receptor site at the protein receptor/membrane bilayer interface. Thus, the design of drugs which target membrane bound receptors should take into consideration the interaction of the drug molecule with the membrane lipid compartment. This understanding of drug/membrane interactions may lead to the development of drugs with more desirable pharmacokinetics, greater efficacy, and reduced side effects. |
| Membrane ion transport in erythrocytes of salt hypertensive Dahl rats and their F2 hybrids: the importance of cholesterol Vokurkova, M., Z. Dobesova, et al. (2003), Hypertens Res 26(5): 397-404. Abstract: The possible association of salt hypertension and altered lipid metabolism with abnormalities of particular systems transporting sodium and potassium has been studied in erythrocytes of Dahl rats and their F2 hybrids fed a high-salt diet since weaning. Our attention was paid to the Na(+)-K+ pump, Na(+)-K+ cotransport and especially to passive membrane permeability for Na+ and Rb+ (Na+ and Rb+ leak), because the Na+ leak was found to be dependent on the genotype, age and salt intake of Dahl rats, whereas the Rb+ leak was suggested to be a potential marker of salt sensitivity in Dahl and Sabra rats. Young male Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats kept on a low-salt (0.3% NaCl) or high-salt diet (8% NaCl) were used for the progenitor study. The subsequent genetic study was based on 135 young male SS/Jr x SR/Jr F2 hybrids fed a high-salt diet since weaning. Ouabain (5 mmol/l) and bumetanide (10 micromol/l) were used to distinguish the contribution of the Na(+)-K+ pump, Na(+)-K+ cotransport and passive membrane permeability to measured net Na+ fluxes and unidirectional Rb+ (K+) movements. Compared to normotensive SR/Jr animals, salt-loaded SS/Jr rats had higher blood pressure (BP), elevated erythrocyte Na+ content, and increased Na+ and Rb+ leaks together with enhanced Na+ and Rb+ transport mediated by the Na(+)-K+ pump and Na(+)-K+ cotransport system. Salt hypertensive Dahl rats were also characterized by elevated plasma levels of total cholesterol and triglycerides, which were positively associated with BP of F2 hybrids (r=0.27 and 0.24, p< 0.01). In F2 hybrids, mean arterial pressure correlated significantly with erythrocyte Na+ content (r=0.24, p<0.01) and ouabain-sensitive Na+ extrusion, but not with the passive membrane permeability for Na+ or Rb+ (r=-0.02 and 0.06, not significant). Both of the above-mentioned significant associations could partially be ascribed to the dependence of erythrocyte Na+ content and ouabain-sensitive Na+ extrusion on plasma cholesterol (r=0.18 and 0.21, p<0.05). Our results support the idea that abnormal lipid metabolism and/or altered Na+,K(+)-ATPase function play an important role in the pathogenesis of salt hypertension in salt-sensitive Dahl rats. |
| Membrane lipid domains distinct from cholesterol/sphingomyelin-rich rafts are involved in the ABCA1-mediated lipid secretory pathway Mendez, A. J., G. Lin, et al. (2001), J Biol Chem 276(5): 3158-66. Abstract: Efflux of excess cellular cholesterol mediated by lipid-poor apolipoproteins occurs by an active mechanism distinct from passive diffusion and is controlled by the ATP-binding cassette transporter ABCA1. Here we examined whether ABCA1-mediated lipid efflux involves the selective removal of lipids associated with membrane rafts, plasma membrane domains enriched in cholesterol and sphingomyelin. ABCA1 was not associated with cholesterol and sphingolipid-rich membrane raft domains based on detergent solubility and lack of colocalization with marker proteins associated with raft domains. Lipid efflux to apoA-I was accounted for by decreases in cellular lipids not associated with cholesterol/sphingomyelin-rich membranes. Treating cells with filipin, to disrupt raft structure, or with sphingomyelinase, to digest plasma membrane sphingomyelin, did not impair apoA-I-mediated cholesterol or phosphatidylcholine efflux. In contrast, efflux of cholesterol to high density lipoproteins (HDL) or plasma was partially accounted for by depletion of cholesterol from membrane rafts. Additionally, HDL-mediated cholesterol efflux was partially inhibited by filipin and sphingomyelinase treatment. Apo-A-I-mediated cholesterol efflux was absent from fibroblasts with nonfunctional ABCA1 (Tangier disease cells), despite near normal amounts of cholesterol associated with raft domains and normal abilities of plasma and HDL to deplete cholesterol from these domains. Thus, the involvement of membrane rafts in cholesterol efflux applies to lipidated HDL particles but not to lipid-free apoA-I. We conclude that cholesterol and sphingomyelin-rich membrane rafts do not provide lipid for efflux promoted by apolipoproteins through the ABCA1-mediated lipid secretory pathway and that ABCA1 is not associated with these domains. |
| Membrane organization at low cholesterol concentrations: a study using 7-nitrobenz-2-oxa-1,3-diazol-4-yl-labeled cholesterol Mukherjee, S. and A. Chattopadhyay (1996), Biochemistry 35(4): 1311-22. Abstract: Cholesterol is most often found distributed nonrandomly in the plane of the bilayer, giving rise to cholesterol-rich and -poor domains. Many of these domains are thought to be crucial for the maintenance of membrane structure and function. However, such well-characterized domains generally occur in the membranes that contain relatively large amounts of cholesterol. Cholesterol organization in membranes containing very low amounts of cholesterol has not been investigated extensively. Recent evidence from differential-scanning calorimetric studies suggest that cholesterol may not form uniform monodisperse solutions, as assumed earlier, in the membranes even at very low concentrations. Fluorescent cholesterol analogues, when chosen carefully, offer a powerful approach for studying the distribution and organization of cholesterol in membranes at low concentrations. In this paper, we have studied the organization of cholesterol in membranes at very low concentrations (up to 5 mol % of the total lipid) using a fluorescent cholesterol analogue (NBD-cholesterol) which is labeled with the 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) group at the flexible acyl chain, without any alteration in the structural features necessary for proper membrane incorporation. Our results show that NBD-cholesterol exhibits local organization even at very low concentrations. This is consistent with the recently suggested model of cholesterol organization in membranes at low concentrations, involving the formation of transbilayer, tail-to-tail dimers Harris, J.S., Epps, D. E., Davio, S. R., & Kezdy, F.J. (1995) Biochemistry 34, 3851-3857. The implications of such local cholesterol organization in membranes that have very low cholesterol content in vivo, such as the endoplasmic reticulum and the inner mitochondrial membrane, open up interesting possibilities. |
| Membrane ruffling and macropinocytosis in A431 cells require cholesterol Grimmer, S., B. van Deurs, et al. (2002), J Cell Sci 115(Pt 14): 2953-62. Abstract: Cholesterol is important for the formation of caveolea and deeply invaginated clathrin-coated pits. We have now investigated whether formation of macropinosomes is dependent on the presence of cholesterol in the plasma membrane. Macropinocytosis in A431 cells was induced by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate, a potent activator of protein kinase C (PKC). When cells were pretreated with methyl-beta-cyclodextrin to extract cholesterol, the phorbol ester was unable to induce the increased endocytosis of ricin otherwise seen, although PKC could still be activated. Electron microscopy revealed that extraction of cholesterol inhibited the formation of membrane ruffles and macropinosomes at the plasma membrane. Furthermore, cholesterol depletion inhibited the phorbol ester-induced reorganization of filamentous actin at the cell periphery, a prerequisite for the formation of membrane ruffles that close into macropinosomes. Under normal conditions the small GTPase Rac1 is activated by the phorbol ester and subsequently localized to the plasma membrane, where it induces the reorganization of actin filaments required for formation of membrane ruffles. Cholesterol depletion did not inhibit the activation of Rac1. However, confocal microscopy showed that extraction of cholesterol prevented the phorbol ester-stimulated localization of Rac1 to the plasma membrane. Thus, our results demonstrate that cholesterol is required for the membrane localization of activated Rac1, actin reorganization, membrane ruffling and macropinocytosis. |
| Membrane-bound enzymes of cholesterol synthesis from lanosterol Gaylor, J. L. (2002), Biochem Biophys Res Commun 292(5): 1139-46. |
| Membrane-dependent conformational changes initiate cholesterol-dependent cytolysin oligomerization and intersubunit beta-strand alignment Ramachandran, R., R. K. Tweten, et al. (2004), Nat Struct Mol Biol 11(8): 697-705. Abstract: Cholesterol-dependent cytolysins are bacterial protein toxins that bind to cholesterol-containing membranes, form oligomeric complexes and insert into the bilayer to create large aqueous pores. Membrane-dependent structural rearrangements required to initiate the oligomerization of perfringolysin O monomers have been identified, as have the monomer-monomer interaction surfaces, using site-specific mutagenesis, disulfide trapping and multiple fluorescence techniques. Upon binding to the membrane, a structural element in perfringolysin O moves to expose the edge of a previously hidden beta-strand that forms the monomer-monomer interface and is required for oligomer assembly. The beta-strands that form the interface each contain a single aromatic residue, and these aromatics appear to stack, thereby aligning the transmembrane beta-hairpins of adjacent monomers in the proper register for insertion. Collectively, these data reveal a novel membrane binding-dependent mechanism for regulating cytolysin monomer-monomer association and pore formation. |
| Membrane-protein interactions contribute to efficient 27-hydroxylation of cholesterol by mitochondrial cytochrome P450 27A1 Murtazina, D., A. V. Puchkaev, et al. (2002), J Biol Chem 277(40): 37582-9. Abstract: Mitochondrial cytochrome P450 27A1 (P450 27A1) catalyzes 27-hydroxylation of cholesterol, the first step in the alternative bile acid biosynthetic pathway. Although several crystal structures of P450s are known, no structural information is available for the mammalian, membrane-bound enzymes involved in the removal of cholesterol from the body. We prepared a three-dimensional model of P450 27A1 based on the structure of P450 BM-3. Conservative and non-conservative mutations were introduced at hydrophobic and positively charged residues in the putative F-G loop and the adjacent helix G (positions 219-237). Subcellular distribution of the mutant P450s expressed in Escherichia coli was used as a measure of membrane-protein interactions. Conservative substitutions of residues located on the surface, according to our model, L219V, L219I, Y220F, F223Y, L224I, R229K, V231L, F234Y, K236R, and R237K, weakened the association of the mutant P450s with the membrane and led to the appearance of up to 21% of P450 27A1 in the bacterial cytosol. It is likely that the mutated side chains are involved in binding to membrane phospholipids. Substitutions in the F-G loop did not significantly affect the K(m) value for cholesterol hydroxylation. However, non-conservative mutants, L219N, Y220A, Y220S, F223A, K226R, and R229A, had significantly impaired catalytic properties, indicating strict requirements for the size and polarity of the side chains at these positions for the catalysis. The results provide insight into the membrane topology of mitochondrial P450s and indicate the importance of membrane-protein interactions in the efficiency of reactions catalyzed by P450 27A1. |
| Men classified as hypo- or hyperresponders to dietary cholesterol feeding exhibit differences in lipoprotein metabolism Herron, K. L., S. Vega-Lopez, et al. (2003), J Nutr 133(4): 1036-42. Abstract: The purpose of this study was to evaluate the differences that occur within the plasma compartment of normolipidemic men, classified on the basis of their response to prolonged consumption of additional dietary cholesterol. Using a crossover design, 40 men aged 18-57 y were randomly allocated to an egg (640 mg/d additional dietary cholesterol) or placebo group (0 mg/d additional dietary cholesterol), for two 30-d periods, which were separated by a 3-wk washout period. Subjects were classified as hypo- increase in plasma total cholesterol (TC) of <0.05 mmol/L for each additional 100 mg of dietary cholesterol consumed or hyperresponders (increase in TC of > or =0.06 mmol/L for each additional 100 mg of dietary cholesterol consumed) on the basis of their plasma reaction to the additional dietary cholesterol provided. Male hyporesponders did not experience an increase in LDL cholesterol (LDL-C) or HDL cholesterol (HDL-C) during the egg period, whereas both lipoproteins were significantly (P < 0.0001 and P < 0.05, respectively) elevated in hyperresponders. Although the LDL/HDL ratio was increased in male hyperresponders after the high cholesterol period, the mean increase experienced by this population was still within National Cholesterol Education Program guidelines. Furthermore, male hyperresponders had higher lecithin cholesterol acyltransferase (P < 0.05) and cholesteryl ester transfer protein (P < 0.05) activities during the egg period, which suggests an increase in reverse cholesterol transport. These data suggest that additional dietary cholesterol does not increase the risk of developing an atherogenic lipoprotein profile in healthy men, regardless of their response classification. |
| Menopause and serum cholesterol: differences between blacks and whites. The Minnesota Heart Survey Demirovic, J., J. M. Sprafka, et al. (1992), Am J Epidemiol 136(2): 155-64. Abstract: The relation between menopause and serum total and high-density-lipoprotein cholesterol was examined by the Minnesota Heart Survey in a cross-sectional, population-based study of 344 black women and 474 white women aged 35-54 years from the Twin Cities metropolitan area in 1985-1986. Analysis of covariance was used to examine differences in serum total and high-density-lipoprotein cholesterol in black women and white women by menopausal status, adjusting for the effects of age, educational level, cigarette smoking, body mass index, exercise, alcohol consumption, diabetes mellitus, sex hormone, beta blocker, and diuretic use. Among whites, adjusted serum total cholesterol was 13 mg/dl higher in postmenopausal than in premenopausal women (p less than 0.002). Black postmenopausal women had slightly higher serum total cholesterol than did their premenopausal counterparts (5.4 mg/dl). However, this was not statistically significant. An interaction term in a linear regression model confirmed a racial difference in the total cholesterol association with menopause (p less than 0.02). The higher total cholesterol levels observed in white postmenopausal women were mainly among those with natural menopause (20.7 mg/dl higher than premenopausal, p less than 0.0003) and those with a hysterectomy and at least one intact ovary (11.0 mg/dl higher, p = 0.05). Among black women, only the subgroup with a hysterectomy and a bilateral oophorectomy had a significantly higher serum total cholesterol (19.9 mg/dl higher than premenopausal, p less than 0.05). There was no significant association between high-density-lipoprotein cholesterol and any type of menopause in either black women or white women. Our findings may reflect a true physiologic difference in the relation between menopause and serum total cholesterol between American blacks and whites. The lack of a significant association between menopause and high-density-lipoprotein cholesterol in either race raises the possibility that menopause may not affect atherosclerosis risk via reduced high-density-lipoprotein cholesterol. |