| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Risks of cholesterol-lowering therapies Hibbeln, J. R. and N. Salem, Jr. (1996), Biol Psychiatry 40(7): 686-7. |
| RLP-C (remnant-like particle cholesterol) Iwashima, Y. (1998), Nippon Rinsho 56 Suppl 3: 262-8. |
| RNA editing: a novel mechanism for the regulation of dietary cholesterol absorption. The Humphry Davy Rolleston lecture 1989 Scott, J. (1990), J R Coll Physicians Lond 24(2): 101-6. |
| Ro 48-8.071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastatin Morand, O. H., J. D. Aebi, et al. (1997), J Lipid Res 38(2): 373-90. Abstract: 2,3-Oxidosqualene:lanosterol cyclase (OSC, E.C. 5.4.99.7) represents a unique target for a cholesterol lowering drug. Partial inhibition of OSC should reduce synthesis of lanosterol and subsequent sterols, and also stimulate the production of epoxysterols that repress HMG-CoA reductase expression, generating a synergistic, self-limited negative regulatory loop. Hence, the pharmacological properties of Ro 48-8.071, a new OSC inhibitor, were compared to that of an HMG-CoA reductase inhibitor, simvastatin. Ro 48-8.071 blocked human liver OSC and cholesterol synthesis in HepG2 cells in the nanomolar range; in cells it triggered the production of monooxidosqualene, dioxidosqualene, and epoxycholesterol. It was safe in hamsters, squirrel monkeys and Gottingen minipigs at pharmacologically active doses, lowering LDL approximately 60% in hamsters, and at least 30% in the two other species, being at least as efficacious as safe doses of simvastatin. The latter was hepatotoxic in hamsters at doses > 30 mumol/kg/day limiting its window of efficacy. Hepatic monooxidosqualene increased dose-dependently after treatment with Ro 48-8.071, up to approximately 20 micrograms/g wet liver or less than 1% of hepatic cholesterol, and it was inversely correlated with LDL levels. Ro 48-8.071 did not reduce coenzyme Q10 levels in liver and heart of hamsters, and importantly did not trigger an overexpression of hepatic HMG-CoA reductase, squalene synthase, and OSC itself. In strong contrast, simvastatin stimulated these enzymes dramatically, and reduced coenzyme Q10 levels in liver and heart. Altogether these findings clearly differentiate the OSC inhibitor Ro 48-8.071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway. |
| Rod-like cholesterol micelles in aqueous solution studied using polarized and depolarized dynamic light scattering Castanho, M. A., W. Brown, et al. (1992), Biophys J 63(6): 1455-61. Abstract: Micelles of cholesterol in aqueous solution have been investigated using polarized and depolarized dynamic light scattering. They are shown to be highly extended and characterized by a narrow size distribution. It is shown that a rod-like model is applicable with length, L = 580 nm. Determination of the rotational diffusion coefficient by analysis of the autocorrelation function gave a value of theta = 150 s-1, which is close to the calculated value for the rod with this dimension. Depolarized dynamic light scattering measurements as a function of angle gave a value of 110 s-1. |
| Role for human immunodeficiency virus type 1 membrane cholesterol in viral internalization Guyader, M., E. Kiyokawa, et al. (2002), J Virol 76(20): 10356-64. Abstract: The membrane of human immunodeficiency virus type 1 (HIV-1) virions contains high levels of cholesterol and sphingomyelin, an enrichment that is explained by the preferential budding of the virus through raft microdomains of the plasma membrane. Upon depletion of cholesterol from HIV-1 virions with methyl-beta-cyclodextrin, infectivity was almost completely abolished. In contrast, this treatment had only a mild effect on the infectiousness of particles pseudotyped with the G envelope of vesicular stomatitis virus. The cholesterol-chelating compound nystatin had a similar effect. Cholesterol-depleted HIV-1 virions exhibited wild-type patterns of viral proteins and contained normal levels of cyclophilin A and glycosylphosphatidylinositol-anchored proteins. Nevertheless, and although they could still bind target cells, these virions were markedly defective for internalization. These results indicate that the cholesterol present in the HIV-1 membrane plays a prominent role in the fusion process that is key to viral entry and suggest that drugs capable of disturbing the lipid composition of virions could serve as a basis for the development of microbicides. |
| Role for influenza virus envelope cholesterol in virus entry and infection Sun, X. and G. R. Whittaker (2003), J Virol 77(23): 12543-51. Abstract: Enveloped viruses are highly dependent on their lipid envelopes for entry into and infection of host cells. Here, we have examined the role of cholesterol in the virus envelope, using methyl-beta-cyclodextrin depletion. Pretreatment of virions with methyl-beta-cyclodextrin efficiently depleted envelope cholesterol from influenza virus and significantly reduced virus infectivity in a dose-dependent manner. A nonenveloped virus, simian virus 40, was not affected by methyl-beta-cyclodextrin treatment. In the case of influenza virus, infectivity could be partially rescued by the addition of exogenous cholesterol. Influenza virus morphology, binding, and internalization were not affected by methyl-beta-cyclodextrin depletion, whereas envelope cholesterol depletion markedly affected influenza virus fusion, as measured by a specific reduction in the infectivity of viruses induced to fuse at the cell surface and by fluorescence-dequenching assays. These data suggest that envelope cholesterol is a critical factor in the fusion process of influenza virus. |
| Role for sterol regulatory element binding protein in the regulation of farnesyl diphosphate synthase and in the control of cellular levels of cholesterol and triglyceride: evidence from sterol regulation-defective cells Jackson, S. M., J. Ericsson, et al. (1996), J Lipid Res 37(8): 1712-21. Abstract: In order to define the factors involved in the regulation of farnesyl diphosphate (FPP) synthase, we used sterol regulation-defective (SRD) cell lines that constitutively express either high (SRD-2) or low (SRD-6) levels of transcriptionally active sterol regulatory element binding protein (SREBP). FPP synthase mRNA levels were high in SRD-2 cells and low in SRD-6 cells and were unaffected by the addition or removal of sterols from the media. In contrast, the mRNA levels in parental CHO-7 cells were regulated by sterols. SRD-2, SRD-6, and CHO-7 cells were also transiently transfected with plasmids containing FPP synthase promoter-reporter genes. Reporter gene activity was significantly higher in SRD-2 cells than in either SRD-6 or CHO-7 cells, consistent with a higher rate of transcription of the reporter gene in SRD-2 cells. The high expression of the reporter gene in SRD-2 cells was not observed when the FPP synthase promoter contained a three base pair mutation within an SREBP binding site, termed sterol regulatory element-3 (SRE-3). These observations are consistent with the hypothesis that high levels of transcription of the FPP synthase gene are dependent on the availability of transcriptionally active SREBP. We also demonstrate that the incorporation of radioactive acetate into both cholesterol and fatty acids was enhanced in SRD-2 cells as compared to CHO-7 or SRD-6 cells. Finally, we demonstrate that the concentrations of cholesterol, cholesteryl ester, and triglyceride were all significantly elevated in SRD-2 cells. We conclude that SREBP is involved not only in the regulation of FPP synthase and cholesterogenesis but also in fatty acid and triglyceride synthesis. |
| Role of ABC transporters in secretion of cholesterol from liver into bile Small, D. M. (2003), Proc Natl Acad Sci U S A 100(1): 4-6. |
| Role of ABC1 gene in cholesterol efflux and atheroprotection Owen, J. S. (1999), Lancet 354(9188): 1402-3. |
| Role of ABCA1 in cellular cholesterol efflux and reverse cholesterol transport Tall, A. R. (2003), Arterioscler Thromb Vasc Biol 23(5): 710-1. |
| Role of acetoin on the regulation of intermediate metabolism of Ehrlich ascites tumor mitochondria: its contribution to membrane cholesterol enrichment modifying passive proton permeability Baggetto, L. G. and R. Testa-Parussini (1990), Arch Biochem Biophys 283(2): 241-8. Abstract: Acetoin, an unusual metabolite of highly glycolytic mammalian tumor cells, is synthesized from decarboxylated pyruvate and active acetaldehyde in mitochondria. It plays important roles in the regulation and detoxification of pyruvate metabolism through pyruvate dehydrogenase. We show in this report the inhibitory effect of acetoin on succinate oxidation by Ehrlich tumor cell mitochondria, and thus its regulatory role on intermediate metabolism. Acetoin utilization by Ehrlich mitochondria may lead to small quantities of citrate formation which increase the already increased cholesterol synthesis of cancer cells. Membranes, in particular the inner mitochondrial membrane, flooded with cholesterol, show a proton passive permeability twice as low as that of control mitochondrial membranes, a feature that may be related to drastic changes in membrane potential-dependent metabolism of cancer cells. |
| Role of acyl coenzyme A cholesterol acyltransferase in intrahepatic processing of apo B-lipoprotein in suncus Nagayoshi, A., N. Matsuki, et al. (1995), J Biochem (Tokyo) 118(2): 259-64. Abstract: We have previously shown that fatty liver was easily induced in suncus by starvation and that the plasma level of apolipoprotein B (apoB) was very low. We also previously reported that a defect in the assembling process of apo B-containing lipoprotein (very low density lipoprotein, VLDL) may be one of the reasons for the low level of plasma apo B and for induction of fatty liver by starvation in suncus. We also found that hepatic acyl coenzyme A cholesterol acyltransferase (ACAT) activity is very low in the animals, resulting in decreased cholesteryl ester contents in the liver. A deficiency of cholesteryl ester in suncus liver may be one of the reasons for the defect in the assembling process of VLDL. In this study, we investigated the effect of cholesterol-feeding, which induces an increase in triglyceride and cholesteryl ester of the liver as a consequence of the induction of both intestinal and hepatic ACAT activities, on the secretion of VLDL. Although the basal ACAT activity of intestinal mucosa was high, cholesterol-feeding did not induce either an increase in plasma lipid or an increase in intestinal ACAT activities in suncus. The hepatic secretion rate of VLDL was estimated by treatment with Triton WR1339, which is well known to inhibit the catabolism of VLDL. Cholesterol-feeding caused a slight increase in hepatic triglyceride and cholesteryl ester but no increase either in the secretion rate of VLDL or in hepatic ACAT activity.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Role of acyl-coenzyme a: cholesterol acyltransferase activity in the processing of the amyloid precursor protein Puglielli, L., B. C. Ellis, et al. (2004), J Mol Neurosci 24(1): 93-6. Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory deficit, cognitive impairment, and personality changes accompanied by specific structural abnormalities in the brain. Deposition of amyloid-beta (Abeta) peptide into senile plaques is a consistent feature of the brains of patients affected by AD. Studies with both animal and cellular models of AD have shown that cholesterol homeostasis and distribution regulate Abeta generation. We have provided genetic, biochemical, and metabolic evidence that implicates intracellular cholesterol distribution, rather than total cholesterol levels, in the regulation of Abeta generation. This minireview focuses on the role of acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) in Abeta generation. In genetically mutant cell lines that overproduce cholesterol but cannot synthesize cholesteryl esters (CEs) because of deficient ACAT activity, Abeta production is almost completely inhibited. Acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) inhibitors, currently being developed for the treatment and prevention of atherosclerosis, reduce CE levels and Abeta generation by up to 50% in cell culture models of AD. Future mechanistic and transgenic animal studies are needed to evaluate the potential use of ACAT inhibitors in the therapeutic treatment or prevention of AD. |
| Role of acyl-coenzyme A:cholesterol acyltransferase-1 in the control of hepatic very low density lipoprotein secretion and low density lipoprotein receptor expression in the mouse and hamster Spady, D. K., M. N. Willard, et al. (2000), J Biol Chem 275(35): 27005-12. Abstract: Cholesteryl esters present in nascent very low density lipoproteins are generated in a reaction catalyzed by acyl CoA:cholesterol acyltransferase (ACAT). To examine the effect of cholesteryl esters on the secretion of apoB-containing lipoproteins, we transiently overexpressed human (h) ACAT-1 in the livers of low density lipoprotein (LDL) receptor(-/-) mice using adenovirus-mediated gene transfer. Overexpression of hACAT-1 increased hepatic total and esterified cholesterol but did not reduce hepatic free cholesterol due to a compensatory increase in the rate of de novo cholesterol synthesis. Overexpression of hACAT-1 markedly increased the plasma concentration and hepatic secretion of apoB-containing lipoproteins but had no effect on the clearance of very low density lipoprotein-apoB from plasma indicating that cholesteryl esters play an important role in regulating the assembly and secretion of apoB-containing lipoproteins. ACAT activity has been implicated in the regulation of the LDL receptor pathway by dietary fatty acids. It has been hypothesized that unsaturated fatty acids, by enhancing ACAT activity, reduce the amount of free cholesterol in a putative regulatory pool that feeds back on LDL receptor expression. We directly tested this hypothesis in hamsters by transiently overexpressing hACAT-1 in the liver. Enhanced cholesterol esterification in the liver resulted in a compensatory increase in de novo cholesterol synthesis but no induction of LDL receptor expression suggesting that fatty acids regulate LDL receptor expression via a mechanism independent of ACAT. |
| Role of an N-ethylmaleimide-sensitive factor in the selective cellular uptake of low-density lipoprotein free cholesterol Fielding, C. J. and P. E. Fielding (1995), Biochemistry 34(43): 14237-44. Abstract: Low-density lipoprotein (LDL) was the major contributor to an influx of free sterol from plasma which balances high-density lipoprotein (HDL)-mediated efflux from cultured skin fibroblasts. When HDL was absent, the uptake of LDL free cholesterol was associated with an increase in total cell cholesterol, due in part to accumulation of esterified cholesterol. This influx was mediated by a high-capacity, low-affinity pathway whose magnitude was similar in normal and LDL receptor-deficient cells. In the presence of HDL, some of the interiorized labeled LDL free cholesterol became available for HDL-mediated efflux and some was interiorized, as a result of a transport mechanism which was sensitive to N-ethylmaleimide (NEM) and nitrate ion but resistant to progesterone, azide, or vanadate. We suggest that normal free cholesterol homeostasis in these cells includes the initial binding of LDL followed by the selective transfer of free cholesterol to a compartment from which it is either returned to the membrane for efflux or internalized for storage or further metabolism within the cell. In the presence of NEM, LDL-derived free cholesterol remained mostly accessible for efflux from the cell surface. This free cholesterol pathway may function physiologically to stabilize plasma membrane cholesterol levels against the effect of varying concentrations of HDL and LDL. |
| Role of apolipoprotein A-I in cholesterol transfer between lipoproteins. Evidence for involvement of specific apoA-I domains Meng, Q. H., J. Bergeron, et al. (1995), J Biol Chem 270(15): 8588-96. Abstract: A series of monoclonal antibodies against epitopes spanning different domains of apoA-I have been tested for their effects on unesterified cholesterol transfer between low density lipoprotein (LDL) and well-defined homogenous lipoproteins reconstituted with phosphatidylcholine, cholesterol, and apoA-I (LpA-I). Antibodies 2G11 (reacting between residues 25 and 110), A05 (residues 25-82), A03 (residues 135-140), A44 and r5G9 (residues 149-186), and 4A12 (residues 173-205) significantly inhibit cholesterol transfer from LDL to Lp2A-I while they enhance transfer in the opposite direction, thus causing an increased net transfer to LDL. Most of these monoclonal antibodies (mAbs) also enhance phospholipid transfer to LDL but in a lesser and variable proportion relative to cholesterol. Their epitopes are mainly contained within domains that are predicted to be amphipathic alpha-helices. In contrast, mAbs 4H1 (residues 2-8), 3G10 (residues 96-121), and 5F6 (residues 116-141) have little or no effect on either cholesterol or phospholipid transfer, and the epitopes for these three mAbs have been shown in earlier studies to be structurally and functionally related. Their immunoreactivity responds similarly to variation in lipoprotein cholesterol content, and the antibodies binding to these sites compete with one another and have similar effects on the cholesterol esterification reaction. Thus, the current results are compatible with the hypothesis that they form an integrated domain with a common function in cholesterol metabolism, possibly as part of a hinge domain. Most mAbs were found to increase significantly the alpha-helicity of apoA-I in the Lp2A-I immunecomplexes, suggesting that they may increase the stability of the lipid-bound apoA-I. However, not unexpectedly, there is no correlation between the effects of mAbs on alpha-helicity and their effects on cholesterol or phospholipid transfer since each mAb has a discrete effect on these transfers. These studies demonstrate the specificity of LpA-I particles in cholesterol transport and document the existence of apoA-I domains with different functions in cholesterol transport. |
| Role of apolipoprotein E and B gene variation in determining response of lipid, lipoprotein, and apolipoprotein levels to increased dietary cholesterol Boerwinkle, E., S. A. Brown, et al. (1991), Am J Hum Genet 49(6): 1145-54. Abstract: A large segment of the population is modifying its dietary cholesterol intake to achieve a healthier life-style. However, all individuals do not respond equally. We have investigated the effects that that two physiologically important polymorphisms in the apolipoprotein (apo) E and B genes have on the responses of plasma lipid, lipoprotein, and apolipoprotein levels to a high-cholesterol diet. Over a 6-wk period, individuals were prescribed two diets, one consisting of 300 mg dietary cholesterol/d for 3 wk and one consisting of 1,700 mg dietary cholesterol/d for 3 wk. Total cholesterol, low-density-lipoprotein cholesterol (LDL-C), and apo B levels were significantly increased on the high-cholesterol diet. Average total cholesterol (numbers in parentheses are SDs) went from 167.6 (23.4) mg/dl on the low-cholesterol diet to 190.8 (36.2) mg/dl on the high-cholesterol diet; LDL-C went from 99.9 (24.8) mg/dl to 119.2 (33.4) mg/dl, and apo B went from 74.9 (24.5) mg/dl to 86.8 (29.5) mg/dl. In 71 individuals, the frequencies of the apo epsilon 2, epsilon 3, and epsilon 4 alleles were.09.84, and.07, respectively. The frequency of the longer, apo B signal peptide allele (5'beta SP27) was.68. Apo epsilon 2/3 individuals had significantly lower LDL-C levels than did epsilon 3/3 homozygotes, on both the low-cholesterol diet (LDL-C lower by 21 mg/dl) and the high-cholesterol diet (LDL-C lower by 27 mg/dl). Average triglyceride levels were significantly different among apo B signal peptide genotypes, with the 5'beta SP27/37 homozygotes having the lowest levels (70 mg/dl). When individuals were switched from the low-cholesterol diet to the high-cholesterol diet, in no case were the average responses in lipid levels significantly different among apo E or B genotypes. Therefore, these gene loci do not have a major effect on the response of lipid levels to increased dietary cholesterol. |
| Role of apolipoproteins A-I, A-II and C-I in cholesterol efflux from endothelial and smooth muscle cells Savion, N. and S. Kotev-Emeth (1993), Eur Heart J 14(7): 930-5. Abstract: The role of purified apolipoproteins A-I, A-II and C-I in the process of cholesterol efflux from cultured vascular endothelial and smooth muscle cells was studied. 3HCholesterol pre-labelled cultures were exposed to serum-free medium supplemented with free apolipoproteins or with apolipoproteins and phosphatidylcholine liposomes and the cholesterol efflux from the cells was determined. Free apolipoproteins A-I and A-II supported cholesterol efflux from vascular endothelial and smooth muscle cells to a higher extent than apolipoprotein C-I. The ability of free apolipoproteins A-I and A-II to support cholesterol efflux was in correlation with their specific binding to the cultures, while no specific binding of apolipoprotein C-I was detected. The association of apolipoprotein A-I with phosphatidylcholine liposomes resulted in a more than two-fold increase in cholesterol efflux compared to free apolipoprotein A-I, while association of apolipoproteins A-II and C-I with phosphatidylcholine liposomes resulted in a very limited increase in cholesterol efflux above that achieved by the free apolipoproteins. These results suggest that apolipoprotein A-I is involved in cholesterol efflux performed by high density lipoprotein. Furthermore, free apolipoproteins A-I and A-II, but not apolipoprotein C-I may take an active part in cholesterol efflux from endothelial and smooth muscle cells. |
| Role of apolipoproteins in cholesterol efflux from macrophages to lipid microemulsion: proposal of a putative model for the pre-beta high-density lipoprotein pathway Hara, H. and S. Yokoyama (1992), Biochemistry 31(7): 2040-6. Abstract: Lipid microemulsion of phospholipid and triglyceride with the size of low-density lipoprotein was capable of removing cholesterol from cholesterol-loaded mouse peritoneal macrophages, resulting in reduction of intracellularly accumulated cholesteryl ester. Apolipoproteins (apo) A-I, A-II, C-III, and E bound to the surface of the microemulsion did not modulate the interaction of the microemulsion with the cells in terms of the cholesterol efflux. The cholesterol removal by the microemulsion was enhanced by some 30% only when apoA-I, -A-II, and -E were present in excess to provide their free forms in the medium, but apoC-III did not show such an effect even by its excess amount. The kinetics including the results with apoC-III were consistent with a model that the apparent enhancement was due to generation of pre-beta high-density lipoprotein (HDL)-like particles upon the interaction of free apolipoproteins with macrophages Hara, H., & Yokoyama, S. (1991) J. Biol. Chem. 266, 3080-3086. However, pre beta-HDL-like particle was not detected after 6- and 24-h incubation in the medium where cholesterol efflux to the emulsion was maximally enhanced by the apolipoproteins, and cholesterol and phospholipids removed from the cells were all found with the microemulsions. It was also shown separately that the lipids in pre beta-HDL-like particles generated by apoA-I and macrophages were rapidly, within the order of minutes, transferred to the apo-lipoprotein-covered microemulsions when they were incubated together. Thus, the data were consistent with a model that the free form of certain apolipoproteins, such as apoA-I, -A-II, and -E but not apoC-III, generates pre beta-HDL-like particles with cellular lipids in situ and these particles act as mediators for cholesterol transfer from the cells to other lipoproteins. |