| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| United States Cholesterol Guidelines 2001: expanded scope of intensive low-density lipoprotein-lowering therapy Grundy, S. M. (2001), Am J Cardiol 88(7B): 23J-27J. Abstract: The new clinical guidelines of the US National Cholesterol Education Program (NCEP) were released in May 2001. These guidelines were published as the NCEP's Adult Treatment Panel (ATP) III report. They are derived from an extensive review of the emerging literature so as to provide an evidence-based report. Thanks to recent clinical trials of cholesterol-lowering therapy, it is possible to expand the scope of clinical management for both dietary and drug therapies. This expansion derives from a conclusive demonstration of efficacy, safety, and cost-effectiveness of therapies. This article will review briefly the major features of ATP III. |
| Unrealistic cholesterol levels Overby, A. (2004), Lakartidningen 101(48): 3944; author reply 3944. |
| Unreliability of rate constants derived from a linear transformation of kinetic data, with special reference to cholesterol equilibration between phospholipid vesicles Gains, N. (1992), Biochem J 283 (Pt 2): 537-9. Abstract: In the time-dependent transfer of a lipid from a donor to an acceptor vesicle population a(t) is the amount transferred to the acceptor vesicles at time t, a infinity is the equilibrium transfer value and a0 is the value at zero time. In order to plot kinetic data (a(t) as ln(a infinity - a(t))/(a infinity - a(t)) against time and to fit these with a linear regression, it is necessary to know the equilibrium value, a infinity, or to choose one. Here it is shown that even if a very larger error is made in the choice of a infinity, the resulting plot can still be acceptably linear and the correlation coefficient of the regression acceptably high. When a infinity is overestimated the rate constant derived from the slope of such a plot is underestimated. In extreme cases a 10-fold error can occur. |
| Unresolved issues in early trials of cholesterol lowering LaRosa, J. C. (1995), Am J Cardiol 76(9): 5C-9C. Abstract: A reexamination of early intervention trials in patients with coronary artery disease (CAD) shows that a pessimistic view of cholesterol reduction in such patients is inappropriate. In observational studies, individuals with documented coronary artery disease and elevated cholesterol levels fare worse than individuals with normal or low cholesterol levels. Early trials of cholesterol reduction in individuals with coronary artery disease succeeded in lowering total cholesterol levels by only 5-15%. Nevertheless, when reviewed in meta-analysis, these trials demonstrated borderline effects on total mortality, statistically significant benefits in terms of morbidity and mortality due to cardiovascular disease and CAD, and no increase in mortality from noncardiovascular causes. Substantially greater lowering of low density lipoprotein (LDL) levels was achieved in early regression studies. In these studies, examples of improvement were noted in individual coronary artery segments. What was not appreciated initially was the dramatic reduction in coronary events. Older secondary prevention trials did not definitively address the benefits of cholesterol reduction in individuals whose cholesterol levels were only modestly elevated (total cholesterol, 160-240 mg/dl 4.14-6.21 mmol/liter, and LDL cholesterol levels 100-160 mg/dl 2.59-4.14 mmol/liter). Several other issues were not addressed in these early studies, including the effect of declines in triglyceride levels, increases in high density lipoprotein (HDL) levels, and the effects in women and individuals aged > 60 years. Even with these limitations, a comparison of meta-analyses of other medical interventions--i.e. beta blockade and aspirin therapy--indicates that declines in coronary mortality are in the same range as obtained in older studies with modest cholesterol reduction--i.e., 20-25%.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Unsaturated fatty acids incorporated in HDL in hypo- and hyperalphalipoproteinemia--relation to the HDL-cholesterol level Vecera, R., Z. Chmela, et al. (1994), Acta Univ Palacki Olomuc Fac Med 137: 35-8. Abstract: Proportions of unsaturated fatty acids of high density lipoprotein (HDL) lipids and their relationships to the HDL-cholesterol level were compared in hypo- and hyperalphalipoproteinemic subjects. Both groups did not differ in the level of serum cholesterol. However, hypoalphalipoproteinemia was associated with hypertriglyceridemia, higher HDL-triacylglycerol level, and higher proportion of HDL-18:1 (oleic acid) and lower proportions of HDL-18:2 (linoleic acid) and 20:4 (arachidonic acid) than hyperalphalipoproteinemia. The HDL-20:4 was the only fatty acid correlating (negatively) with HDL-cholesterol. However, HDL-18:1 correlated positively and HDL-18:2 negatively with HDL-triacylglycerols, lipids related to the fall of HDL-cholesterol. These results suggest 1) an antagonism of 20:4 and 18:2 as structural components of HDL lipids in relation to the HDL-cholesterol level, and 2) an association of replacement of HDL 18:2 by 18:1 with the disorder of plasma triacylglycerol metabolism. |
| Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1 Wang, Y. and J. F. Oram (2002), J Biol Chem 277(7): 5692-7. Abstract: Abnormal high density lipoprotein metabolism may contribute to the increased atherosclerosis associated with diabetes and insulin resistance. The ATP-binding cassette transporter ABCA1 mediates cholesterol transport from tissue macrophages to apoA-I, the major high density lipoprotein protein component. Because fatty acids are elevated in diabetes, we examined the effects of fatty acids on ABCA1 activity in cultured macrophages. Results showed that unsaturated fatty acids markedly inhibited ABCA1-mediated cholesterol and phospholipid efflux from macrophages when ABCA1 was induced by a cAMP analog. This was accompanied by a reduction in the membrane content of ABCA1 and a decrease in apoA-I binding to whole cells and to ABCA1. In contrast, saturated fatty acids had no effect on these processes. Fatty acids did not alter ABCA1 mRNA abundance or incorporation of methionine into ABCA1, indicating that decreased ABCA1 transcription, enhanced mRNA decay, or impaired translation efficiency did not account for these inhibitory effects. Unsaturated fatty acids, however, increased ABCA1 turnover when protein synthesis was blocked by cycloheximide. We conclude that unsaturated fatty acids reduce the macrophage ABCA1 content by enhancing its degradation rate. These findings raise the possibility that an increased supply of unsaturated fatty acids in the artery wall promotes atherogenesis by impairing the ABCA1 cholesterol secretory pathway in macrophages. |
| Unusual cholesterol esters in the sebum of young children Stewart, M. E. and D. T. Downing (1990), J Invest Dermatol 95(5): 603-6. Abstract: Cholesterol esters (CE) having fatty acids of more than 18 carbons are a prominent feature of fetal skin surface lipid (vernix caseosa), but are a minor component of adult lipid. The difference may be related to the fact that fetal sebaceous glands generally synthesize little lipid. If so, it would be expected that prepuberal children, who also have very inactive glands, would secrete CE with a large proportion of very-long-chain fatty acids. To test this conjecture, skin surface CE from young children were isolated and analyzed. Sebum was extracted from the hair of 38 children, aged six to nine. To obtain a measure of sebaceous lipogenesis, the class composition of the lipid was determined by quantitative thin-layer chromatography and the ratio of wax esters/cholesterol + cholesterol esters (WE/CH + CE) was calculated. CE were then isolated from the lipid and hydrolyzed. The freed fatty acids were converted to fatty acid methyl esters (FAME) and analyzed by capillary gas chromatography to determine the proportion with more than 18 carbons. FAME from five of the subjects were then separated into saturated and monounsaturated fractions and analyzed again by gas chromatography to identify chain types. Ratios of WE/CH + CE ranged from 0.08 to 2.8 in the subjects. The proportion of CE FAME with more than 18 carbons ranged from 15 to 72%, with the highest proportion being found in the children with the lowest WE/CH + CE. The saturated FAME were mostly iso- or anteiso-branched, whereas the monounsaturated FAME were mostly straight-chain extension products of 16: 1 delta 9 or 18: 1 delta 9. |
| Unusual product ratios resulting from the gamma-irradiation of cholesterol in liposomes Maerker, G. and K. C. Jones (1991), Lipids 26(2): 139-44. Abstract: Cholesterol in aqueous suspensions of multilamellar vesicles (MLV) was exposed to gamma-irradiation (0.5-10 kGy) at 0-4 degrees C. Cholesterol oxidation products resulting from the irradiation were isolated by dry column extraction followed by preparative thin-layer chromatography (TLC) and were quantitated by on-column gas chromatography (GC). The ratio of 7-ketocholesterol/cholesterol 5,6-epoxides generated by irradiation was less than one, much lower than the ratio of ten commonly produced by autoxidation. Irradiation also produced relatively higher amounts of 7-hydroxycholesterol than did autoxidation. These unique product ratios may be suitable indicators of past exposure to irradiation. |
| Update on cholesterol and the eye Nishimoto, J. H. (1995), Optom Clin 4(3): 41-52. Abstract: High serum cholesterol levels have been accepted as a major risk factor for cardiovascular disease and arteriosclerosis. There are several corneal signs that potentially indicate abnormal cholesterol levels, thus altering the eye care practitioner to refer the patient for lipid evaluation. This article describes the corneal manifestations of abnormal cholesterol levels and offers guidelines for management. |
| Update on the National Cholesterol Education Program Adult Treatment Panel III guidelines: getting to goal McKenney, J. M. (2003), Pharmacotherapy 23(9 Pt 2): 26S-33S. Abstract: Considerable data on the pathophysiology, epidemiology, and treatment of dyslipidemia-induced coronary heart disease (CHD) have accumulated in recent years. These data have been assessed and incorporated into the guidelines of the National Cholesterol Education Program Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel ATP III). A major focus of the new guidelines is the assessment of the near-term (i.e., 10-yr) risk of experiencing a CHD event and matching the intensity of treatment to this risk. Patients with diabetes and those with a greater than 20% 10-year risk of experiencing a CHD event have been elevated to the risk level of CHD equivalent. The ATP III guidelines also modify several lipid and lipoprotein classifications. A low-density lipoprotein cholesterol (LDL) level below 100 mg/dl is now considered optimum for all individuals. In addition, high-density lipoprotein cholesterol (HDL) and triglyceride cutoff points have been modified to reflect more accurately the risk associated with abnormalities in these lipoproteins. As with the previous guidelines, the primary target of therapy remains LDL. Therapeutic lifestyle changes consisting of diet, weight reduction, and increased physical activity should be included in all treatment regimens. Based on their potent LDL-lowering properties and their proven ability to decrease mortality in a variety of patient populations, statins are generally the first choice for pharmacologic therapy. A secondary target of therapy includes non-HDL goals for patients with high triglyceride levels and the metabolic syndrome, which is characterized by abdominal obesity, elevated triglyceride levels, low HDL levels, and insulin resistance. Management of these secondary targets includes weight reduction and increased physical activity, and treatment of the lipid and nonlipid risk factors. Overall, ATP III represents an aggressive approach to treating dyslipidemia, greatly extending the number of individuals who qualify for treatment. |
| Updated guidelines for cholesterol management Lauer, M. S. and P. B. Fontanarosa (2001), Jama 285(19): 2508-9. |
| Updated guidelines support even lower cholesterol levels for at-risk patients Levenson, D. (2004), Rep Med Guidel Outcomes Res 15(15): 1, 6-7. |
| Up-regulation of acyl-coenzyme A:cholesterol acyltransferase (ACAT) in nephrotic syndrome Vaziri, N. D. and K. Liang (2002), Kidney Int 61(5): 1769-75. Abstract: BACKGROUND: We have previously demonstrated that hypercholesterolemia in rats with puromycin-induced nephrotic syndrome (NS) is associated with up-regulation of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and relative down-regulation of cholesterol 7alpha-hydroxylase (Ch-7alpha), which represent the rate-limiting steps in cholesterol biosynthesis and catabolism. Expression of HMG-CoA reductase is inhibited and Ch-7alpha is augmented by intracellular free cholesterol, which is avidly esterified by acyl-CoA:cholesterol acyltransferase (ACAT). Therefore, we hypothesized that NS may result in up-regulation of hepatic ACAT. METHODS: Hepatic tissue ACAT mRNA (Northern blot), protein (Western blot) and enzymatic activity were determined in rats with puromycin-induced NS, placebo-treated control rats and Nagase hypoalbuminemic (NAG) rats. RESULTS: The NS group exhibited heavy proteinuria, hypoalbuminemia, normal creatinine clearance, severe hypercholesterolemia and hypertriglyceridemia. Despite severe hypoalbuminemia, NAG rats with inherited hypoalbuminemia exhibited only a mild elevation of plasma cholesterol and triglycerides. Severe hypercholesterolemia in the NS group was coupled with depressed liver tissue free cholesterol concentration and marked increases in hepatic ACAT mRNA, protein and enzymatic activity. In contrast, ACAT mRNA and protein contents of the liver were normal and ACAT activity was mildly elevated in the NAG group. CONCLUSIONS: NS results in marked up-regulation of hepatic ACAT, which is primarily due to proteinuria and not hypoalbuminemia, since the latter alone, as seen in NAG rats, does not significantly impact ACAT expression. Elevated ACAT in NS can contribute to dysregulation of cholesterol biosynthesis and catabolism by limiting the normal cholesterol signaling involved in regulation of these processes. |
| Upregulation of cholesterol synthesis after acute myocardial infarction--is cholesterol a positive acute phase reactant? Pfohl, M., I. Schreiber, et al. (1999), Atherosclerosis 142(2): 389-93. Abstract: Acute myocardial infarction is associated with profound alterations in the plasma lipoprotein profile. The mechanism of these alterations is not clear, and both cholesterol biosynthesis up- and downregulation could possibly be a consequence of acute myocardial infarction. We determined plasma lipids, lipoproteins, apolipoproteins, and lathosterol-which is regarded as an estimate of whole body cholesterol biosynthesis in humans-concentrations in 34 patients (age 68+/-10 years, 24 male, 10 female) admitted to our hospital with acute MI and with onset of symptoms within the last 12 h. Samples were taken immediately after admission to the hospital, and 1, 2, and 10 days after admission. On the first day after admission there was a decrease in total cholesterol (C) by 14.1%, (P = 0.01), in LDL-C by 14.4% (P = 0.03), in HDL-C by 9.3% (NS), and in triglycerides by 19.5% (NS). Apolipoprotein B100 was reduced by 18.3% (P = 0.008), and apolipoprotein AI by 12.3% (NS). The lathosterol/cholesterol ratio was increased by 23.1% after 1 day, and by 28.7% after 2 days (P = 0.05). After 10 days, all variables except the apolipoproteins had essentially returned to baseline values. In conclusion, the changes in the plasma lipid profile after acute myocardial infarction are associated with a profound increase of whole body cholesterol biosynthesis as judged by the lathosterol/cholesterol ratio. These changes may possibly enhance the delivery of cholesterol to cells involved in tissue repair mechanisms after acute myocardial infarction. |
| Upregulation of cholesterol synthesis after acute reduction of low density lipoprotein by apheresis in normocholesterolaemic subjects: evidence for a threshold effect Pfohl, M., R. P. Naoumova, et al. (1997), Atherosclerosis 135(2): 257-62. Abstract: The influence of low density lipoproteins (LDL) in the plasma on the regulation of cholesterol biosynthesis is not clear. We studied the changes in plasma mevalonic acid (MVA) concentration and the lathosterol/cholesterol (L/C) ratio, which are well established indices of whole body cholesterol synthesis, in four normocholesterolaemic subjects after each had undergone LDL apheresis on two occasions. LDL apheresis of 75% of the calculated plasma volume reduced LDL-cholesterol by 44% to 1.5 +/- 0.2 mmol/l without changing plasma MVA levels or L/C ratios. Apheresis of 125% of the calculated plasma volume decreased plasma LDL-cholesterol by 69% to 0.9 +/- 0.2 mmol/l, with significant increases in plasma MVA and L/C ratio on the day after the procedure. These results imply that LDL-cholesterol is an integral part of the sterol regulatory pool and suggest that plasma levels cannot be lowered below 1-1.4 mmol/l in normal subjects without upregulating cholesterol biosynthesis. |
| Up-regulation of hepatic LDL receptor gene expression by monatepil, a novel calcium antagonist, in high cholesterol diet-fed Japanese monkeys Notake, M., Y. Kondo, et al. (1994), Am J Hypertens 7(11): 1026-30. Abstract: The action of the novel antihypertensive calcium antagonist monatepil on the hepatic LDL receptor was investigated at the gene expression level to clarify the mechanism of its hypolipidemic effect. In cholesterol-fed control monkeys, the LDL receptor mRNA level decreased to approximately 30% of that in the normal diet-fed monkeys. However, the administration of monatepil increased LDL receptor mRNA to normal levels (three- to fourfold stimulation). It is suggested that monatepil raises the number of LDL receptors in liver tissue and that this increase may accelerate the removal of plasma LDL. Treatment with prazosin, an alpha 1-adrenoceptor antagonist, also increased the LDL receptor mRNA level, but this restorative effect was much weaker than that of monatepil, suggesting that mechanisms additional to its alpha 1-adrenoceptor blocking activity are involved in the hypolipidemic effect of monatepil. |
| Up-regulation of low-density lipoprotein receptor in human hepatocytes is induced by sequestration of free cholesterol in the endosomal/lysosomal compartment Issandou, M., R. Guillard, et al. (2004), Biochem Pharmacol 67(12): 2281-9. Abstract: Up-regulation of low-density lipoprotein receptor (LDLr) is a key mechanism to control elevated plasma LDL-cholesterol levels. In the present paper, we compare the ability of four distinct pharmacological drugs to up-regulate LDLr expression in human hepatocytes. HepG2 cells were treated with the steroidal analog GW707, the oxidosqualene cyclase inhibitor U18666A, the 3beta-hydroxysterol Delta(7)-reductase inhibitor AY-9944 and the vacuolar-type ATPase inhibitor bafilomycin A1. We found that the four compounds induced sequestration of free cholesterol in the endosomal/lysosomal compartment leading to a positive filipin staining pattern and a complete inhibition of cholesteryl ester synthesis. As a consequence of the sequestration of cholesterol, the expression and the activity of LDLr were strongly induced resulting from a transcriptional effect which was measured by a reporter gene assay. These effects were fully abolished when an exogenous water soluble cholesterol analog was added to the cells. These findings have led to the identification of a common mechanism to up-regulate LDLr expression in human hepatocytes and may represent an interesting alternative approach to identify new hypolipidemic drugs. |
| Up-regulation of the fibrogenic cytokine TGF-beta1 by oxysterols: a mechanistic link between cholesterol and atherosclerosis Leonarduzzi, G., A. Sevanian, et al. (2001), Faseb J 15(9): 1619-21. |
| Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides Coon, H., Y. Xin, et al. (2005), Hum Genet 117(5): 444-51. Abstract: Positive evidence has been reported for linkage and association between the upstream stimulatory factor 1 gene (USF1) and familial combined hyperlipidemia (FCHL). We genotyped the two most positive single-nucleotide polymorphisms (SNPs) (usf1s1: rs3737787 and usf1s2: rs2073658) from previous studies in a large family sample. This sample included 2,195 subjects in 87 Utah pedigrees ascertained for early death due to coronary heart disease (CHD), early strokes, or early onset hypertension. There were a total of 262 relative pairs in these families with FCHL. In the full family sample, FCHL was associated with usf1s1 (P = 0.02). Triglyceride and LDL cholesterol defined qualitatively or quantitatively were also associated with usf1s1 (P = 0.02-0.05). Results were strengthened for qualitative and quantitative triglyceride and LDL cholesterol when data from males only was analyzed, revealing associations for usf1s1 (P = 0.001-0.02), usf1s2 (P = 0.02-0.05) and the haplotype of these two SNPs (P = 0.01-0.04). The strongest results were in the subset of subjects from families ascertained for premature stroke or hypertension, rather than those ascertained for premature CHD. This study replicates the involvement of USF1 in FCHL and related lipid traits in a family sample not ascertained for FCHL. |
| Uptake and metabolism of dolichol and cholesterol in perfused rat liver Kalen, A., M. Soderberg, et al. (1990), Lipids 25(2): 93-9. Abstract: The uptake of dolichol and cholesterol by perfused rat liver was studied. When these radioactive lipids were incorporated into egg phosphatidylcholine liposomes, both dolichol and cholesterol appeared initially in the supernatant and in the microsomal fraction and, later on, in the mitochondrial-lysosomal fraction. The lipids taken up were esterified to some extent, but no phosphorylation of dolichol occurred. Incorporation of dolichol and cholesterol into lipoproteins increased the efficiency of uptake, which was receptor-mediated in this case. Accumulation of these lipids occurred in lysosomes followed by a transport to the endoplasmic reticulum (ER). Both labeled dolichol and cholesterol appeared in the bile. In the case of dolichol, the majority of this radioactivity was not associated with the original substance itself, and probably represented lipid-soluble catabolites. In the case of cholesterol, most of the radioactivity was associated with bile acids. It appears that, in contrast to the receptor-mediated uptake of lipoproteins from the perfusate, the uptake of liposomal lipids involves a different mechanism. After association with the plasma membrane, the lipids enter into the cytoplasm and are transported to the ER and later to the lysosomes. |