| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| The efficacy of atorvastatin in treating patients with hypercholesterolaemia to target LDL-cholesterol goals: the LIPI-GOAL trial Muls, E., G. De Backer, et al. (2001), Acta Cardiol 56(2): 109-14. Abstract: OBJECTIVE: LIPI-GOAL is a multicentre, open-label, non-comparative treat-to-target study, conducted from March 1998 to May 1999, that assessed the percentage of patients reaching 1992 European Atherosclerosis Society (EAS) low-density lipoprotein cholesterol (LDL-C) targets with atorvastatin 10-80 mg/day in subjects with hypercholesterolaemia, defined as LDL-C > 160 mg/dl after a 12-week step I diet. METHODS AND RESULTS: Patients were treated towards the following LDL-C goals: < 135 mg/dl in patients with atherosclerotic disease present and/or coronary heart disease (CHD) risk >40%/10 years, or LDL-C < 155 mg/dl in all others. All subjects started treatment with atorvastatin 10 mg/day for 6 weeks. The dose was doubled every 6 weeks, to 20, 40, or 80 mg/day at weeks 12, 18, and 24, respectively, if targets were not reached. Of 587 patients screened for participation, 473 were enrolled and 419 (59% male; mean age 61 years) were available for efficacy evaluation. Fifty-five percent had atherosclerotic disease and/or CHD risk >40%/10 years. Dose titration was not needed in 303 patients (72%) who reached LDL-C target with atorvastatin 10 mg/day. Among 116 patients who were subsequently treated with higher atorvastatin dosages, 47 reached LDL-C target with 20 mg/day, 15 with 40 mg/day, and 6 with 80 mg/day. Therefore, 88.5% of subjects reached LDL-C goal in an intention-to-treat analysis. In general, atorvastatin was well tolerated. CONCLUSIONS: Most patients at high risk for CHD reached LDL-C goals with atorvastatin 10-80 mg/day. Seventy-two % of patients reached target with atorvastatin 10 mg/day, which may simplify clinical management and should encourage better adherence to recommendations. |
| The efficacy of cholesterol-lowering action and side effects of garlic enteric coated tablets in man Tanamai, J., S. Veeramanomai, et al. (2004), J Med Assoc Thai 87(10): 1156-61. Abstract: The present study aimed at investigating the cholesterol-lowering and side effects of garlic enteric coated tablets in comparison with placebo tablets. The study is a randomized double-blinded crossover design involving 116 volunteers. However, 16 of them did not complete the study. The remaining 100 volunteers were divided into two groups: 45 were in the trial group and the remaining 55 in the control group. The volunteers in the trial group were asked to take garlic tablets in the first three months, placebo in the second three months and discontinue all tablets in the last three months, while the volunteers in the control group started with three months of placebo followed by three months of garlic tablets and ended up with three months of tablets discontinuity. The results showed that there were no significant differences in the total serum cholesterol levels between the two groups at the end of three months or six months of the study. Side effects included headache, itching and complaints of garlic smell. No serious side effects relating to liver, kidney functions or hematologic side effects were detected |
| The efficacy of lovastatin in lowering cholesterol in African Americans with primary hypercholesterolemia Fong, R. L. and H. J. Ward (1997), Am J Med 102(4): 387-91. Abstract: PURPOSE: To evaluate the efficacy of lovastatin in African Americans (AA) diagnosed with primary hypercholesterolemia. PATIENTS AND METHODS: Forty-seven AA patients from the King/Drew Medical Center in Los Angeles were recruited from the Hypertension, Family Practice, and General Medicine Clinics for a double-blinded, placebo-controlled trial. Forty-one patients completed the 10 week study. Eligibility for entrance into the study was determined by patient lipid profiles meeting the criteria for pharmacological intervention outlined by the National Cholesterol Education Program II guidelines. Patients were randomized into 2 groups: lovastatin 20 mg per day, or placebo. A registered dietitian counseled both groups on two visits during the study to ensure compliance with a low fat, low cholesterol diet. Lipid levels were compared at the first and last visit of the study. RESULTS: The lovastatin-treated group demonstrated significant reductions in mean total cholesterol (TC) (14.7%, 95% confidence interval CI-6.6 to -22.8, P < 0.01) and low-density lipoprotein (LDL) cholesterol (20.0%, 95% CI-7.9 to -32.1, P < 0.01) from baseline. Plasma triglyceride (TG) levels decreased by 10.5% (95% CI-2.4 to -18.6) and total cholesterol/high density lipoprotein (HDL) ratio fell below five in the lovastatin group, but neither reduction reached statistical significance. Placebo administration was not associated with any significant changes in TC, LDL, or TG. There were no significant differences between baseline and post-treatment hepatic transaminase levels in either group. CONCLUSIONS: The HMG-CoA (3-hydroxyl-3 methylglutary coenzyme A) reductase inhibitor lovastatin in a dose of 20 mg per day was effective in decreasing TC, LDL, and TG levels in an AA population. Considering that the AA population is at substantially increased risk for hypertension and cardiovascular morbidity, more aggressive and wider use of HMG-CoA reductase inhibitors should be employed in reducing elevated plasma cholesterol levels. |
| The efflux of lysosomal cholesterol from cells Johnson, W. J., G. K. Chacko, et al. (1990), J Biol Chem 265(10): 5546-53. Abstract: To gain insight into the transport of sterol from lysosomes to the plasma membrane, we studied the efflux of lysosomal free cholesterol from intact Fu5AH rat hepatoma cells to high density lipoprotein (HDL) and other extracellular acceptors that promote sterol desorption from the plasma membrane. The procedures involved pulsing cells at 15 degrees C with low density lipoprotein that had been reconstituted with 3Hcholesteryl oleate and then incubating the cells at 37 degrees C in the presence of a sterol acceptor, while monitoring both the hydrolysis of 3Hcholesteryl oleate in lysosomes and the efflux of the resulting 3Hfree cholesterol to the acceptor. After warming cells to 37 degrees C, rapid hydrolysis of 3Hcholesteryl oleate began after 10-20 min, and the lysosomally generated 3Hfree cholesterol became available for efflux after an additional delay of 40-50 min. The kinetics of hydrolysis and the delay between hydrolysis and efflux were unchanged over a wide range of HDL3 concentrations (10-1000 micrograms of protein/ml), and with acceptors that do not interact with HDL-specific cell surface binding sites (phospholipid vesicles, dimethyl suberimidate cross-linked HDL). In addition, the delivery of lysosomal cholesterol to the plasma membrane was unaffected when cellular cholesterol content was elevated 2.6-fold above the normal control level, or when the activity of cellular acyl-coenzyme A/cholesterol acyltransferase (ACAT) was stimulated with exogenous oleic acid. We conclude that in the Fu5AH cell, a maximum of 40-50 min is required for the transport of cholesterol from lysosomes to the plasma membrane and that this transport is not regulated in response to either specific extracellular acceptors or the content of sterol in cells. The lack of effect of increased ACAT activity implies that the pathway for this transport does not involve passage of sterol through the rough endoplasmic reticulum, the subcellular location of ACAT. |
| The elevation of plasma concentration of high-density lipoprotein cholesterol in mice fed with protein from proso millet Nishizawa, N. and Y. Fudamoto (1995), Biosci Biotechnol Biochem 59(2): 333-5. Abstract: We examined the effects of dietary proso-millet protein on plasma concentration of high-density lipoprotein (HDL) cholesterol in mice. The results confirmed also, in this animal, the elevation of plasma concentration of HDL cholesterol without the involvement in raising the concentration of low-density lipoprotein cholesterol like those with rats reported in our previous paper. This would suggest a beneficial effect of millet protein on cholesterol metabolism. |
| The emerging role of HDL cholesterol. Is it time to focus more energy on raising high-density lipoprotein levels? Safeer, R. S. and M. O. Cornell (2000), Postgrad Med 108(7): 87-90, 93-8. Abstract: Low HDL cholesterol levels have been found to be a risk factor for CAD. To date, the focus of treating hyperlipidemia has been on lowering LDL cholesterol levels. Now, as more and more compelling data are reported, it is time to begin focusing more energy on how to raise HDL cholesterol levels. If exercise, smoking cessation, and moderate alcohol consumption fail to achieve HDL cholesterol goals, niacin, fibric acid derivatives, or statin drugs may prove helpful in patients at high risk of CAD. |
| The emerging role of lipoproteins in atherogenesis: beyond LDL cholesterol Nicholls, S. and P. Lundman (2004), Semin Vasc Med 4(2): 187-95. Abstract: Low-density lipoprotein cholesterol has a well-established role in atherogenesis and the development of coronary heart disease. However, despite effective lowering of low-density lipoprotein cholesterol, many patients continue to have cardiovascular events. It has subsequently emerged that several additional dyslipidemic states promote atherogenesis. In particular, the atherogenic lipoprotein phenotype comprising an elevation of triglycerides and triglyceride-rich lipoproteins; decreased concentrations of high-density lipoprotein cholesterol; and increased small, dense low-density lipoprotein cholesterol, in addition to impaired postprandial lipemia, have been demonstrated to have profound effects on the arterial wall. As such, these factors have become important targets in the development of effective strategies to prevent atherosclerotic cardiovascular disease. |
| The enantiomer of cholesterol Westover, E. J. and D. F. Covey (2004), J Membr Biol 202(2): 61-72. Abstract: Cholesterol plays a variety of significant roles in biological systems. However, the mechanisms by which cholesterol functions remain largely unclear. The enantiomer of cholesterol (ent-cholesterol)--which has identical physical properties, but opposite three-dimensional configuration compared to cholesterol--is a unique tool that can be used to better understand the mechanisms of cholesterol function. We review the literature pertaining to ent-cholesterol, focusing in particular on its use in biological studies. |
| The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages Feng, B., P. M. Yao, et al. (2003), Nat Cell Biol 5(9): 781-92. Abstract: Excess cellular cholesterol induces apoptosis in macrophages, an event likely to promote progression of atherosclerosis. The cellular mechanism of cholesterol-induced apoptosis is unknown but had previously been thought to involve the plasma membrane. Here we report that the unfolded protein response (UPR) in the endoplasmic reticulum is activated in cholesterol-loaded macrophages, resulting in expression of the cell death effector CHOP. Cholesterol loading depletes endoplasmic reticulum calcium stores, an event known to induce the UPR. Furthermore, endoplasmic reticulum calcium depletion, the UPR, caspase-3 activation and apoptosis are markedly inhibited by selective inhibition of cholesterol trafficking to the endoplasmic reticulum, and Chop-/- macrophages are protected from cholesterol-induced apoptosis. We propose that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterol-induced apoptosis in macrophages. |
| The endothelial cholesterol efflux is promoted by the high-density lipoprotein anionic peptide factor Domingo, N., I. Mastellone, et al. (2005), Metabolism 54(8): 1087-94. Abstract: The prevention of atherosclerosis depends on the high-density lipoprotein (HDL) capacity to stimulate the efflux of unesterified cholesterol (UC). We tested here the effects of 2 HDL apolipoproteins, apo A-I and the 7-kd anionic peptide factor (APF), on the UC efflux by human endothelial ECV 304 cells in culture. Apolipoprotein A-I (10 micromol/L) or APF (3.5 micromol/L) in lipid-free forms or small particles (13 nm with apo A-I or 19 nm with APF) were incubated in the presence of 4-14CUC. The phosphatidylcholines (PCs) were present either at a low level (0.35 mmol/L with apo A-I or 0.20 mmol/L with APF) or at a high level (1 mmol/L with apo A-I). We also tested either large 53-nm bile lipoprotein complex-like particles (3.5 micromol/L APF 13 microg/500 microL) with a high PC level (0.65 mmol/L) or a 9-residue synthetic peptide (13 microg/500 microL), derived from the NH2-terminal domain of HDL3-APF, in a lipid-free or low-lipidated (0.20 mmol/L PCs) form. A control was developed in absence of the added compounds. A rapid 4-14CUC efflux mediated by APF added in free form or in 19-nm complexes was 2.2- to 2.3-fold higher than that mediated by apo A-I in free form or in 13-nm particles (P <.05). The level of this high APF-related efflux was comparable with that obtained with the 12-nm native HDLs (10 micromol/L apo A-I) or free PCs (1 mmol/L). The increase in the UC efflux was much more limited (1.4-fold) in the presence of the 53-nm APF/high-PC particles, but it was higher than that mediated by apo A-I. In addition, the efflux mediated by the synthetic peptide, in lipid-free or low-lipidated form, constituted the major part of that related to the full-length APF. Thus, all these particles are very active HDL components, able to act as cholesterol acceptors. Interestingly, we further showed a new anti-atherogenic property of APF as well as its metabolic importance and clinical relevance. By its involvement in the first step of the reverse cholesterol transport, APF could reduce the risk of cardiovascular disease. |
| The enzymatic transformation of water-insoluble reactants in nonaqueous solvents. Conversion of cholesterol to cholest-4-ene-3-one by a Nocardia sp. Reprinted from Biotechnology and Bioengineering, Vol. XVII, Pages 815-826 (1975) Buckland, B. C., P. Dunnill, et al. (2000), Biotechnol Bioeng 67(6): 714-9. Abstract: The rapid conversion of cholesterol to cholestenone by Nocardia in the presence of high proportions of water-immiscible solvent has been demonstrated. At high agitator speeds, the reaction rate was not limited by the rates of transfer of oxygen or cholesterol to the microorganisms. Using 100 g of thawed cells in 200 ml of carbon tetrachloride containing 16% (w/v) cholesterol, at 20 degrees C cholestenone was formed at 7 g/hr. Cells could be separated easily from the organic solvent and reused. After 7 runs (69 hr) the reaction rate had fallen only to half the value for the first run. |
| The epidemiologic basis for population-wide cholesterol reduction in the primary prevention of coronary artery disease Pearson, T. A. (2004), Am J Cardiol 94(9A): 4F-8F. Abstract: A number of recent epidemiologic observations support the need for new and broader strategies to reduce serum cholesterol levels on a population-wide basis. First, the limited data available suggest a halt in the declining incidence of coronary artery disease (CAD) in the United States since 1990, raising concerns about our current strategies to promote primary prevention of CAD. Data from the 1970s and 1980s support a key role for population-wide cholesterol lowering as a strategy to reduce CAD. Second, large and carefully performed surveys support no further reductions in serum cholesterol levels in the US population since 1990. Is this observation and that of stagnating declines of CAD incidence a coincidence? Interestingly, the lack of cholesterol level reduction occurred in the setting of increased use of prescription cholesterol-lowering drugs, suggesting that drug treatment of the highest-risk persons alone will not shift the population curve. Third, the treatment gap persists, with recent population-wide data suggesting that half of all people with hypercholesterolemia (>/=200 mg/dL) are unaware of their condition, only half of those persons aware are treated, and only half of those treated are controlled. Finally, the moderate-risk population (10% to 20% risk of CAD over 10 years) is sizable in the ages recommended for over-the-counter statin use (>/=45 years in men, >/=55 years in women). Risk reduction in this group, which contributes a significant portion of CAD cases, should be part of any program to reduce the population burden of CAD. |
| The epidemiology of low levels of high-density lipoprotein cholesterol in patients with and without coronary artery disease Maron, D. J. (2000), Am J Cardiol 86(12A): 11L-14L. Abstract: Low levels of high-density lipoprotein cholesterol (HDL-C), and elevated total cholesterol-to-HDL-C ratios are independently associated with increased risk of coronary artery disease. In observational studies, every 1-mg/dL increment in HDL-C is associated with a 2% decreased risk of coronary artery disease in men and 3% decreased risk in women. On average, HDL-C levels are lower in men than in women, and are lower in whites than in blacks. Low HDL-C has also been found to be linked to higher risk of ischemic stroke, degree of carotid atherosclerosis, increased atherosclerotic progression as measured by coronary arteriography, higher coronary mortality among people with cardiovascular disease, and the development of coronary artery disease among patients with diabetes mellitus. |
| The epitaxial growth of cholesterol crystals from bile solutions on calcite substrates Frincu, M. C., S. D. Fleming, et al. (2004), J Am Chem Soc 126(25): 7915-24. Abstract: Epitaxial relationships between the surfaces of inorganic and bioorganic crystals can be an important factor in crystal nucleation and growth processes in a variety of biological environments. Crystalline cholesterol monohydrate (ChM), a constituent of both gallstone and atherosclerotic plaques, is often found in association with assorted mineral phases. Using in situ atomic force microscopy (AFM) and well-characterized model bile solutions, the nucleation and epitaxial growth of ChM on calcite (104) surfaces in real-time is demonstrated. The growth rates of individual cholesterol islands formed on calcite substrates were determined at physiological temperatures. Evidence of Ostwald's ripening was also observed under these experimental conditions. The energetics of various (104) calcite/(001) ChM interfaces were calculated to determine the most stable interfacial structure. These simulations suggest that the interface is fully hydrated and that cholesterol hydroxyl groups are preferentially positioned above carbonate ions in the calcite surface. This combination of experimental and theoretical work provides a clearer picture of how preexisting mineral seeds might provide a viable growth template that can reduce the energetic barrier to cholesterol nucleation under some physiological conditions. |
| The establishment of telomerase-immortalized Tangier disease cell lines indicates the existence of an apolipoprotein A-I-inducible but ABCA1-independent cholesterol efflux pathway Walter, M., N. R. Forsyth, et al. (2004), J Biol Chem 279(20): 20866-73. Abstract: Tangier disease (TD) is a human genetic disorder associated with defective apolipoprotein-I-induced lipid efflux and increased atherosclerotic susceptibility. It has been linked to mutations in the ATP-binding cassette protein A1 (ABCA1). Here we describe the establishment of permanent Tangier cell lines using telomerase. Ectopic expression of the catalytic subunit of human telomerase extended the life span of control and TD skin fibroblasts, and (in contrast to immortalization procedures using viral oncogenes) did not impair apolipoprotein A-I-induced lipid efflux. The key characteristics of TD fibroblasts (reduced cholesterol and phospholipid efflux) were observed both in primary and telomerase-immortalized fibroblasts from two unrelated homozygous patients. Surprisingly, the apolipoprotein-inducible cholesterol efflux in TD cells was significantly improved after immortalization (up to 40% of normal values). In contrast to ABCA1-dependent cholesterol efflux, this efflux was not inhibited by brefeldin A, glybenclamide, or intracellular ATP depletion but was inhibited in the presence of cytochalasin D. Apolipoprotein A-I-dependent cholesterol efflux was inversely correlated with the population doubling number in cell culture and was inhibited up to 40% in near-senescent normal diploid fibroblasts. This inhibition was completely reversed by telomerase. Thus ectopic expression of telomerase is a way to circumvent the lack of critical experimental material and represents a major improvement for studying cholesterol efflux pathways in lipid disorders. Our findings indicate the existence of an ABCA1-independent but cytoskeleton-dependent cholesterol removal pathway that may help to prevent early atherosclerosis in Tangier disease but may also be sensitive to aging phenomena ex vivo and possibly in vivo. |
| The esterification of cholesterol in the liver of the chick embryo Shand, J. H., D. W. West, et al. (1994), Biochim Biophys Acta 1213(2): 224-30. Abstract: The development of the chick embryo was characterised by the accumulation of large droplets of lipid in the cytoplasm of the embryonic liver, as revealed by electron microscopy. Analysis of the lipid composition of the livers indicated that this accumulation resulted from a dramatic increase in the cholesteryl ester content of the tissue during the the latter part of the embryonic period. This lipid is apparently derived from yolk cholesterol and may be taken up by the liver in the form of lipoprotein remnants. Significant levels of acyl-CoA: cholesterol acyltransferase (ACAT) activity were expressed in the liver throughout the second half of the developmental period, and this activity was maximal at the time when lipid transfer from the yolk was most intensive. The activity of microsomal cholesterol ester hydrolase (CEH) was very low throughout development, and no CEH activity was detected in the cytosolic fraction. In addition, substantial amounts of a cytosolic protein which inhibits CEH activity were present. Thus the relative activities of these enzymic systems are consistent with the net accumulation of cholesteryl ester which occurs in the liver during development. |
| The esterification of cholesterol in the yolk sac membrane of the alligator embryo Vajda, K., J. H. Shand, et al. (1993), Biochem Soc Trans 21 (Pt 3)(3): 298S. |
| The esterification of cholesterol in the yolk sac membrane of the chick embryo Shand, J. H., D. W. West, et al. (1993), Lipids 28(7): 621-5. Abstract: The uptake of lipid from the yolk by the yolk sac membrane of the chick embryo is accompanied by the rapid esterification of a large proportion of the yolk cholesterol. This could arise from enhanced acyl-CoA:cholesterol acyltransferase (ACAT) activity and/or inhibition of cholesteryl ester hydrolase (CEH) activity. The activity of ACAT was therefore measured in microsomes obtained from yolk sac membranes at various stages of development. A high level of activity (up to 929 pmol of cholesteryl oleate formed per min per mg protein) was found during the second half of this period. Supplementation with exogenous cholesterol stimulated ACAT activity in microsomes obtained from the tissue at the earlier, but not at the later, stages of development suggesting that the enzyme became saturated with microsomal cholesterol as development proceeded. Correlating with this, the concentration of cholesterol in the microsomes increased 4-fold between 9 and 20 d of development. The activity of CEH was very low in the microsomes and could not be detected in the cytosolic fraction. The activity of a protein, which has been shown to function as an inhibitor of CEH, was found to be present at all stages of development. The high activity of ACAT, together with the low activity of CEH and an active CEH inhibitor protein is a combination well suited to promote an essentially unidirectional conversion of cholesterol to cholesteryl ester. This process may be a major determinant of the rate of lipid transfer from the yolk to the embryo. |
| The evaluation of apparatus for measuring capillary cholesterol Menendez Villalva, C., C. Nunez Losada, et al. (1997), Aten Primaria 20(3): 156-7. |
| The expression of a catalytically active cholesterol 7 alpha-hydroxylase cytochrome P450 in Escherichia coli Li, Y. C. and J. Y. Chiang (1991), J Biol Chem 266(29): 19186-91. Abstract: We have recently cloned a full-length cDNA encoding the rat hepatic cholesterol 7 alpha-hydroxylase cytochrome P450 (P450c7) (Li, Y. C., Wang, D. P., and Chiang, J. Y. L. (1990) J. Biol. Chem. 265, 12012-12019), which catalyzes the rate-limiting reaction of bile acid synthesis in the liver. By using the polymerase chain reaction, we have designed two P450c7 cDNAs. One has the second Met codon deleted and the third Thr codon replaced with an Ala. The other lacks codons for the NH2-terminal hydrophobic sequence of amino acids 2-24 (P450c7 delta 2-24). The cDNAs were separately cloned into the expression vector pKK233-2 and transformed into Escherichia coli. After induction with isopropyl-beta-D-thiogalactopyranoside, bacteria harboring recombinant plasmids expressed a polypeptide which reacted with the antibody against cholesterol 7 alpha-hydroxylase in immunoblots. The slightly modified full-length enzyme was expressed to 0.2% of the total bacterial lysate and was located in the membrane fraction, whereas P450c7 delta 2-24 was expressed at a 10-fold higher level (2%), of which 85% was in the cytosol and the remaining associated with the membranes. We have purified P450c7 delta 2-24 which showed a typical reduced-CO difference spectrum of cytochrome P450 and reconstituted cholesterol 7 alpha-hydroxylase activity in the presence of NADPH-cytochrome P450 reductase. P450c7 delta 2-24 has a similar Km for cholesterol (24.6 microM) but a lower Vmax (0.10 nmol/min) and a lower turnover number (1.93 min-1) as compared with the enzyme isolated from rat liver microsomes. The purified P450c7 delta 2-24 has an unique hydrophilic NH2 terminus and contains monomers and dimers in equal amounts. This is the first report demonstrating that a genetically engineered cytochrome P450 enzyme lacking a typical NH2-terminal hydrophobic sequence is mainly cytosolic and catalytically active. |