| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| New method for assaying free and total cholesterol in cultured cells by high-pressure liquid chromatography Hayashi, K., Y. Kuga, et al. (1996), J Atheroscler Thromb 2(2): 117-21. Abstract: We developed a simple, sensitive and accurate method for assaying cellular free and total cholesterol by monitoring 4-cholesten-3-one, a conversion product of the cholesterol oxidase-catalyzed oxidation of the free cholesterol that has a strong chromophoric alpha, beta-unsaturated ketone at 240 nm, using a high-pressure liquid chromatographic system. This method measured picomole quantities of free and total cholesterol and precisely determined their concentrations in cells (10(4) range) in culture using 7 beta-hydroxycholesterol as an internal standard. |
| New method for isolating and quantifying intermediate and beta-very-low-density lipoprotein cholesterol Wikinski, R. L., L. E. Schreier, et al. (1991), Clin Chem 37(11): 1913-6. Abstract: We describe a new method, useful to clinical laboratories, for assessing intermediate density (IDL) or beta-very-low-density (beta-VLDL) lipoprotein cholesterol. The technique involves selective precipitation properties of the qualitative Wieland and Seidel post-electrophoretic method that immobilizes IDL and beta-VLDL in the beta-zone of an agarose slide (Clin Chem 1973;19:1139-41). In our method, we separate low-density lipoprotein (LDL) in a second electrophoretic step, in which LDL moves toward the anode, and then quantify the cholesterol of the above lipoproteins remaining in the precipitate band at the beta-zone. Replicate within-run precision (CV) of 15 aliquots of a sera pool was 10.1%. The correlation with sequential ultracentrifugation of 30 samples was r = 0.96 (P less than 0.001). Serum reference values for 30 normal individuals are 57 +/- 7.0 mg/L. Seven phenotype III hyperlipoproteinemic patients had the highest concentrations of IDL or beta-VLDL cholesterol in serum, 1620 +/- 346 mg/L. |
| New model to study cholesterol uptake in the human intestine in vitro Sviridov, D. D., I. G. Safonova, et al. (1993), J Lipid Res 34(2): 331-9. Abstract: A new model to study cholesterol uptake in the human intestine in vitro is described. Human small intestine organ cultures were incubated with mixed micelles containing bile acid, phospholipid, and cholesterol or its nonabsorbable analogue, sitosterol; trace amounts of labeled cholesterol or sitosterol were added to the micelles. After incubation, the lipids were extracted from the cells and cholesterol and sitosterol uptake was evaluated. Specific cholesterol uptake was determined as a difference between cholesterol and sitosterol uptake. Cholesterol, but not sitosterol, uptake was time- and dose-dependent. Rapid and slow phases of cholesterol uptake were observed. Cholesterol uptake was also temperature-dependent. Removal of epithelial cells from human intestine explants reduced cholesterol, but not sitosterol, uptake. Inhibition of acyl CoA:cholesterol acyltransferase by Sandoz compound 58-035 and treatment with monensin reduced cholesterol uptake, but not sitosterol uptake, in a dose-dependent manner. In contrast, treatment of cultures with an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, lovastatin, stimulated cholesterol, but not sitosterol, uptake in a dose-dependent manner; mevalonic acid reversed the effect of lovastatin. The presented model allows large-scale in vitro studies of different stages of cholesterol absorption in the human intestine. |
| New molecular targets for cholesterol-lowering therapy Izzat, N. N., M. E. Deshazer, et al. (2000), J Pharmacol Exp Ther 293(2): 315-20. Abstract: The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in randomized clinical trials has established that cholesterol-lowering treatment reduces the risk of both cardiovascular and total mortality. This reduction in risk occurs in patients with or without existing cardiovascular disease and in patients with high or average plasma cholesterol concentrations. Aggressive treatment to lower plasma cholesterol has been shown to slow progression of atherosclerosis and in some instances may be as successful as angioplasty in reducing ischemic events. These studies suggest that reduction of plasma cholesterol to levels even below 100 mg/dl might be desirable. New targets for cholesterol-lowering therapy with mechanisms of action different from the statins have been identified. One of these targets is the Na(+)-dependent bile acid transporter that is expressed in the terminal ileum. This protein is responsible for recycling bile acids from the intestine to the liver. Several compounds that demonstrate the ability to decrease transporter activity and to lower plasma cholesterol have been investigated. Absorption of cholesterol from the small intestine is another potential target. Compounds that inhibit cholesterol absorption may act by interacting stoichiometrically with cholesterol within the intestinal lumen or substoichiometrically, presumably within the enterocyte. Finally, the transcriptional regulation of cholesterol 7alpha-hydroxylase by members of the nuclear receptor superfamily provides at least two other molecular targets for cholesterol-lowering drugs. |
| New MspI polymorphism at +83 bp of the human apolipoprotein AI gene: association with increased circulating high density lipoprotein cholesterol levels Wang, X. L., R. Badenhop, et al. (1996), Genet Epidemiol 13(1): 1-10. Abstract: We recently showed that loss of a MspI restriction site in the 5'-end (intron 1) of the apolipoprotein (apo) AI gene is due to a C to T transition (+83 bp) and/or a G to A transition (+84 bp). Since this region may be relevant to the regulation of apo AI gene expression and therefore to plasma high density lipoprotein cholesterol (HDL-C), we explored the association between this MspI polymorphic site and circulating HDL-C levels in 243 healthy Caucasians. There were 143 aged 18-67 years (60 males and 83 females) and 100 aged 6-12 years (58 males and 42 females). We also compared this association with a known MspI polymorphic site, a G to A transition at -75 bp of the apo AI gene. The rare allele (-) frequency for the polymorphism at +83 bp was 4.1% and 22.1% for the polymorphism at -75 bp. Subjects heterozygous for the loss of the MspI restriction site at +83 bp (genotype: M2+-, n = 20) had higher HDL-C levels than M2+2 subjects (mean +/- SD: 1.73 +/- 0.31 vs. 1.41 +/- 0.39 mmol/l, P < 0.05 for adults; 1.71 +/- 0.33 vs. 1.34 +/- 0.29 mmol/l, P < 0.01 for children). Adults with the G to A substitution at -75 bp also had higher HDL-C levels (1.56 +/- 0.36 mmol/l for AA, 1.53 +/- 0.38 mmol/l for GA, and 1.36 +/- 0.38 mmol/l for GG, P < 0.05); this difference was not observed in the children. The MspI polymorphisms at both sites were in linkage disequilibrium. Their joint effect on the HDL-C levels was also significant and individuals with rare alleles (-) at both sites had the highest HDL-C levels. In an analysis of variance, the MspI polymorphism at +83 bp, and at -75 bp and gender independently accounted for 6.5%, 1.7%, and 5.9%, respectively, of the variance in circulating HDL-C levels when age was controlled as a covariate. We conclude that loss of the MspI site by the C to T (+83 bp) and/or the G to A (+84 bp) transitions is highly associated with increased HDL-C levels. The association appears to be more significant than that of the G to A transition at -75 bp. |
| New National Cholesterol Education Program III guidelines for primary prevention lipid-lowering drug therapy: projected impact on the size, sex, and age distribution of the treatment-eligible population Fedder, D. O., C. E. Koro, et al. (2002), Circulation 105(2): 152-6. Abstract: BACKGROUND: The guidelines in the Third Report of the National Cholesterol Education Program (NCEP III) include absolute risk and lower LDL cholesterol (LDL-C) levels to assess eligibility for lipid-lowering drug therapy. We studied the impact of these changes on the size, sex, and age distribution of the target US population using data from the Third Annual National Health and Nutrition Survey (NHANES III) (1988 to 1994). METHODS AND RESULTS: A subsample of NHANES III participants aged 20 to 79 years with known cardiovascular risk factors and LDL-C levels was identified (n=13 589). We assessed their eligibility for drug therapy first using NCEP II guidelines and then using the new NCEP III criteria. We also calculated the number eligible for LDL-C lowering to <100 mg/dL. An estimated 15 million individuals aged 20 to 79 years are eligible for drug therapy under NCEP II; 51% are males, 49% are females, 26% are <45 years old, and 28% are > or =65 years old. Under NCEP III, 36 million would be eligible for treatment; 55% are males, 45% are females, 32% are <45 years old, and 27% are > or =65 years old. This represents a 140% increase in eligibility overall, a 157% increase among males, a 122% increase among females, a 131% increase among those > or =65 years old, and a 201% increase among those < 45 years old. Of treatment-eligible individuals, 26% of males, 24% of females, 39% of elderly, and 14% of those <45 years old are targeted for LDL-C lowering to <100 mg/dL. CONCLUSIONS: The NCEP III guidelines will alter the age and sex distributions of the treatment-eligible population, targeting many more younger (<45 years old) and greater numbers of elderly (> or =65 years) individuals, particularly for aggressive intervention. |
| New perspectives on the management of low levels of high-density lipoprotein cholesterol Harper, C. R. and T. A. Jacobson (1999), Arch Intern Med 159(10): 1049-57. Abstract: A low serum high-density lipoprotein cholesterol (HDL-C) level is a potent predictor of coronary heart disease (CHD). It has been estimated that 11% of US men have isolated low HDL-C levels, and there is uncertainty regarding the management of these patients. A cause-and-effect relationship between low HDL-C levels and CHD is supported by epidemiological, animal, and human clinical studies. We reviewed the structure and function of HDL-C and its role in preventing atherosclerosis. We then suggested an approach to the patient with isolated low HDL-C that may be useful to the primary care physician. An algorithm was proposed for use in patients with existing CHD, while the decision to treat patients without CHD was based on their score on the Framingham Heart Study risk prediction chart. |
| New possibilities for children with Smith-Lemli-Opitz syndrome. A cholesterol synthesis defect discovered Starck, L., I. Bjorkhem, et al. (1995), Lakartidningen 92(37): 3325-6, 3329. |
| New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice Lyons, M. A., H. Wittenburg, et al. (2003), Physiol Genomics 14(3): 225-39. Abstract: Cholesterol gallstone formation is a response to interactions between multiple genes and environmental stimuli. To determine the subset of cholesterol gallstone susceptibility (Lith) genes possessed by strains CAST/Ei (susceptible) and 129S1/SvImJ (resistant), we conducted quantitative trait locus (QTL) analyses of an intercross between these strains. Parental strains and F(1) mice of both genders were evaluated for gallstone formation after consumption of a lithogenic diet for 8 wk. Gallstone susceptibility of strain CAST was predominantly due to cholesterol hypersecretion. Male intercross offspring were genotyped and phenotyped for cholesterol gallstone formation after consumption of the lithogenic diet for 10 wk. Linkage analysis was performed using PSEUDOMARKER software. One significant, new QTL was detected and named Lith13 chromosome (Chr) 5, 30 cM. Statistical analyses and QTL fine mapping suggest this QTL may comprise two closely linked loci. We confirmed the presence of Lith6 (Chr 6). Suggestive QTL were detected on Chrs 1, 2, 5, 14, and 16. The QTL on Chrs 2 and 16 confirmed previously identified, suggestive QTL. Therefore, they were named Lith12 (101 cM) and Lith14 (42 cM), respectively. We identified candidate genes based on known function and location and performed mRNA expression analyses using both parental strains and intercross progeny for preliminary evaluation of their contributions to gallstone formation. Cebpb (Lith12), Pparg (Lith6), and Slc21a1 (Lith6) displayed expression differences. Our work continues to demonstrate the genetic complexity and to elucidate the pathophysiology of cholesterol gallstone formation. It should facilitate the development of new approaches for treating this common human disorder. |
| New roles for PPARs in cholesterol homeostasis Ricote, M. and C. K. Glass (2001), Trends Pharmacol Sci 22(9): 441-3; discussion 444. |
| New sterically stabilized vesicles based on nonionic surfactant, cholesterol, and poly(ethylene glycol)-cholesterol conjugates Beugin, S., K. Edwards, et al. (1998), Biophys J 74(6): 3198-210. Abstract: Monomethoxypoly(ethylene glycol) cholesteryl carbonates (M-PEG-Chol) with polymer chain molecular weights of 1000 (M-PEG1000-Chol) and 2000 (M-PEG2000-Chol) have been newly synthesized and characterized. Their aggregation behavior in mixture with diglycerol hexadecyl ether (C16G2) and cholesterol has been examined by cryotransmission electron microscopy, high-performance gel exclusion chromatography, and quasielastic light scattering. Nonaggregated, stable, unilamellar vesicles were obtained at low polymer levels with optimal shape and size homogeneity at cholesteryl conjugate/ lipids ratios of 10 mol% M-PEG1000-Chol or 5 mol% M-PEG2000-Chol, corresponding to the theoretically predicted brush conformational state of the PEG chains. At 20 mol% M-PEG1000-Chol or 10 mol% M-PEG2000-Chol, the saturation threshold of the C16G2/cholesterol membrane in polymer is exceeded, and open disk-shaped aggregates are seen in coexistence with closed vesicles. Higher levels up to 30 mol% lead to the complete solubilization of the vesicles into disk-like structures of decreasing size with increasing PEG content. This study underlines the bivalent role of M-PEG-Chol derivatives: while behaving as solubilizing surfactants, they provide an efficient steric barrier, preventing the vesicles from aggregation and fusion over a period of at least 2 weeks. |
| New strategy in gene transfection by cationic transfection lipids with a cationic cholesterol Nakanishi, M. (2003), Curr Med Chem 10(14): 1289-96. Abstract: The present article reviews interesting cationic liposomes (cationic transfection lipids) with novel cationic cholesterol derivatives, a new strategy in gene transfection developed by our group and the presently accepted molecular mechanism of gene transfection. Use of confocal laser scanning microscopy and atomic force microscopy in elucidating the molecular mechanism of gene transfection by cationic liposomes is also reviewed using examples from our own work. As delineated below, both the confocal laser scanning microscopic and the atomic force microscopic results advocate for the involvement of the sequential three steps in gene transfection mediated by the cationic liposomes: endocytotic internalization of the lipoplexes (liposome-DNA complexes) into the target cells, endosome-lysosome fusion whereby the DNA gets released from the liposomes and moves towards the nucleus of the target cells and microtubule organization apparently involved in trafficking the transfected foreign genes to lysosomes. Furthermore, the present article also reviews couple of important strategies in gene transfection namely, use of liposomes made from biosurfactants and harnessing efficient gene transfection by activating the membrane-bound receptor molecules. |
| New therapeutic options in the National Cholesterol Education Program Adult Treatment Panel III Talbert, R. L. (2002), Am J Manag Care 8(12 Suppl): S301-7. Abstract: Coronary heart disease (CHD) is a common, costly, and undertreated disorder in the United States, and dyslipidemia is one of its most important modifiable risk factors. Recently, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) published updated guidelines for the treatment of lipid disorders, greatly expanding the number of patients eligible for therapy. In the new recommendations, several significant changes have been made in the identification and management of patients at risk for CHD. Although ATP III maintains that low-density lipoprotein (LDL) cholesterol should be the primary target of lipid-lowering therapy, it identifies non-high-density lipoprotein (HDL) cholesterol (total cholesterol minus HDL cholesterol) as a secondary target in patients with elevated triglycerides. Patients with > or = 2 CHD risk factors should now be assessed for 10-year absolute CHD risk based on the Framingham Point Scale to identify those who require more aggressive treatment. The guidelines also designate a new category, CHD risk equivalent, which recognizes that certain patients have the same high risk as those with established CHD. Diabetes is now identified as a CHD risk equivalent, as are other forms of atherosclerotic disease and multiple risk factors comprising a CHD 10-year risk of > 20%. New lipoprotein classifications are given, and increased emphasis is placed on the metabolic syndrome, a constellation of metabolic risk factors, as a marker for CHD risk. Since adherence poses a major challenge in the management of patients with or at risk for CHD, the new guidelines provide physicians with several strategies for increasing patient compliance. The new guidelines should help physicians better identify and manage patients at risk for CHD, help more patients reach their lipid goals, and thereby decrease cardiovascular morbidity and mortality. |
| New treatment option for decreasing blood cholesterol level--clinical significance of inhibition of both, cholesterol absorption and synthesis Paragh, G., L. Mark, et al. (2004), Orv Hetil 145(15): 805-11. Abstract: In the development of hypercholesterinaemia two factors play an important role. There is the cholesterol-uptake through the gastrointestinal tract, about 300-700 mg daily depending on the diet, on the other hand gastrointestinal tract plays important role in the reabsorption of cholesterol excreted through the bile by the liver, the amount of which takes 1000 mg. It means that about 1300-1700 mg cholesterol is absorbed in the small intestine daily. Previous major studies have demonstrated that statins, the drugs that have been proved to be the most efficient in decreasing the cholesterol level, can decrease both total and cardiovascular mortality. This effect highly depends on the rate of cholesterol level decrease. Thus, their application in higher doses has been recently suggested to reach the target level, which is performed by dose titration. If the desired effect is not achieved with the starting dose of statins, a doubling of dosage only leads to 6% additional LDL-cholesterol level decrease. During long term administration the so called "escape phenomenon" can be observed, which means that the use of these drugs for a longer period reduces their cholesterol decreasing effect. Higher doses increase the risk of adverse effects, and the "escape phenomenon" decreases the effectiveness. To avoid these effects the combination therapy is recommended for use. In combination therapy drugs with different mechanisms of action should be administered, which increase therapeutic effect, but keep the number of adverse effects decreased or unchanged. Concomitant administration of former known lipid lowering agents--beyond enhancing cholesterol level decrease--has unfortunately increased the frequency of adverse effects as well. In this regard, ezetemibe, the cholesterol absorption inhibitor appears to be promising since it selectively decreases the absorption of cholesterol from intestinal epithelial cell, resulting in an 18-22% LDL-cholesterol decrease. At the same time the decreased uptake from the gastrointestinal tract triggers the endogen cholesterol synthesis in the liver. When this process is inhibited by statin, more impressive cholesterol decreasing effect can be reached. Clinical studies with concurrent use of ezetimibe and statin have confirmed this view. Decreasing cholesterol level at more attack points offers a possibility to reach target values without a significant increase in the risk of adverse effects. So with combination and dual inhibition a more significant cholesterol lowering effect can be obtained beside the decrease of side effects. |
| New trends from the USA. The cholesterol campaign is questioned Ravnskov, U. (1993), Lakartidningen 90(28-29): 2528-9. |
| New type of Domiati cheese of potential benefit to people with high blood cholesterol Abou-Zeid, N. A. (1992), J Dairy Res 59(1): 89-94. Abstract: Part of the milk used for manufacturing Domiati cheese was replaced by buttermilk at rates of 0, 20, 30, 40, 50 and 60%. The fat and SNF contents were standardized at 5 and 10% respectively. The hypocholesterolaemic effect of buttermilk when incorporated into cheese was tested with rats by including cheese manufactured with and without buttermilk mixed in their diet at a rate of 30% for a period of 60 d. When the diet containing Domiati cheese free from buttermilk (control cheese) was given to rats, there were highly significant increases in serum and liver cholesterol. However, when part of the milk used in manufacturing Domiati cheese was replaced by buttermilk the increases in serum and liver cholesterol concentrations were reduced. These reductions were proportional to the proportion of buttermilk incorporated in the milk used to manufacture the cheese. When 50% of the milk used for Domiati cheese was replaced by buttermilk the hypercholesterolaemic effect of Domiati cheese was nullified and the serum and liver cholesterol concentrations were restored to their normal values. The effect of replacing 50% of the milk used in the manufacture of Domiati cheese by buttermilk on the quality of the cheese was tested periodically during the ripening period. The buttermilk improved the flavour of the cheese whilst only slightly affecting its ripening. |
| Newer pathogenetic concepts in cholesterol gallstone formation: a unitary hypothesis Holzbach, R. T. (1997), Digestion 58 Suppl 1: 29-32. |
| Newfound gene holds key to cell's cholesterol traffic Pennisi, E. (1997), Science 277(5323): 180-1. |
| Newly synthesized cholesterol in human bile and plasma: quantitation by mass isotopomer distribution analysis Empen, K., K. Lange, et al. (1997), Am J Physiol 272(2 Pt 1): G367-73. Abstract: The purpose of this study was to quantitate the contribution of newly synthesized cholesterol to bile and plasma in humans. Eight healthy volunteers were intravenously infused with 0.125 mmol of 1-(13)Cacetate per kilogram per hour for 15 h. During continuous enteral nutrition, plasma aliquots and samples of duodenal bile were collected hourly. The trimethysilylether of unesterified cholesterol was analyzed by gas chromatography-mass spectrometry for quantitation of the mass fragments M(+0) mass-to-charge ratio (m/z) 368, M(+1) (m/z 369), M(+2) (m/z 370), M(+3) (m/z 371), and M(+4) (m/z 372). The fractional syntheses of plasma and biliary cholesterol were determined using mass isotopomer distribution analysis. After 6 h of infusion, the 13C enrichment of the acetate pool remained constant at 12%. The fractional synthesis increased continuously during 13Cacetate infusion and reached 4.2% and 5.3% in cholesterol of plasma and bile, respectively. Both were highly correlated, but the fractional synthesis of biliary cholesterol exceeded that of plasma (P < 0.05). It may be concluded that the contribution of de novo cholesterol synthesis to bile exceeds that to plasma but is minor in humans. |
| NFkappaB regulates plasma apolipoprotein A-I and high density lipoprotein cholesterol through inhibition of peroxisome proliferator-activated receptor alpha Morishima, A., N. Ohkubo, et al. (2003), J Biol Chem 278(40): 38188-93. Abstract: The levels of plasma HDL cholesterol and apoA-I in NFkappaB p50 subunit-deficient mice were significantly higher than those in wild-type mice under regular and high fat diets, without any significant difference in the level of total cholesterol. To examine the role of NFkappaBin lipid metabolism, we studied its effect on the regulation of apoA-I secretion from human hepatoma HepG2 cells. Lipopolysaccharide-induced activation of NFkappaB reduced the expression of apoA-I mRNA and protein, whereas adenovirus-mediated expression of IkappaBalpha super-repressor ameliorated the reduction. This IkappaBalpha-induced apoA-I increase was blocked by preincubation with MK886, a selective inhibitor of peroxisome proliferator-activated receptor alpha (PPARalpha), suggesting that NFkappaB inactivation induces apoA-I through activation of PPARalpha. To further support this idea, the expression of IkappaBalpha increased apoA-I promoter activity, and this increase was blocked by preincubation with MK886. Mutations in the putative PPARalpha-binding site in the apoA-I promoter or lack of the site abrogated these changes. Taking these results together, inhibition of NFkappaB increases apoA-I and HDL cholesterol through activation of PPARalpha in vivo and in vitro. Our data suggest a new aspect of lipid metabolism and may lead to a new paradigm for prevention and treatment of atherosclerotic disease. |