Cholesterol Journal Articles

Record 11841 to 11860

Standardizing cholesterol measurements
Seccombe, D. W. (1992), Cmaj 146(8): 1375.

Stanol ester margarine alone and with simvastatin lowers serum cholesterol in families with familial hypercholesterolemia caused by the FH-North Karelia mutation
Vuorio, A. F., H. Gylling, et al. (2000), Arterioscler Thromb Vasc Biol 20(2): 500-6.
Abstract: In heterozygous familial hypercholesterolemia (FH), serum low density lipoprotein (LDL) cholesterol levels are already elevated at birth. Premature coronary heart disease occurs in approximately 30% of heterozygous untreated adult patients. Accordingly, to retard development of atherosclerosis, preventive measures for lowering cholesterol should be started even in childhood. To this end, 19 FH families consumed dietary stanol ester for 3 months. Stanol ester margarine lowers the serum cholesterol level by inhibiting cholesterol absorption. Each individual in the study replaced part of his or her daily dietary fat with 25 g of 80% rapeseed oil margarine containing stanol esters (2.24 g/d stanols, mainly sitostanol). The families who consumed this margarine for 12 weeks included 24 children, aged 3 to 13 years, with the North Karelia variant of FH (FH-NK), 4 FH-NK parents, and 16 healthy family members, and a separate group of 12 FH-NK adults who consumed the margarine for 6 weeks and who were on simvastatin therapy (20 or 40 mg/d). Fat-soluble vitamins were measured by high-pressure liquid chromatography, and cholesterol precursor sterols (indexes of cholesterol synthesis) and cholestanol and plant sterols (indexes of cholesterol absorption efficiency) were assayed by gas-liquid chromatography. No side effects occurred. Serum LDL cholesterol levels were reduced by 18% (P<0.001), 11%, 12% (P<0.001), and 20% (P<0.001) in the 4 groups, respectively. The serum campesterol-to-cholesterol ratios fell by 31% (P<0.001), 29%, 23% (P<0.001), and 36% (P<0.001), respectively, suggesting that cholesterol absorption efficiency was inhibited. Serum lathosterol ratios were elevated by 38% (P<0.001), 11%, 15% (P<0.001), and 19% (P<0.001), respectively, suggesting that cholesterol synthesis was compensatorily upregulated. The FH-NK children increased their serum lathosterol ratio more than did the FH-NK adults treated with stanol ester margarine and simvastatin (P<0.01). In the FH-NK children, serum retinol concentration and alpha-tocopherol-to-cholesterol ratios were unchanged by stanol ester margarine, but alpha- and beta-carotene concentrations and ratios were decreased. As assayed in a genetically defined population of FH patients, a dietary regimen with stanol ester margarine proved to be a safe and effective hypolipidemic treatment for children and adults. In FH-NK adults on simvastatin therapy, serum LDL cholesterol levels could be reduced even further by including a stanol ester margarine in the regimen.

Stanol esters as a component of maximal dietary therapy in the National Cholesterol Education Program Adult Treatment Panel III report
Grundy, S. M. (2005), Am J Cardiol 96(1A): 47D-50D.
Abstract: Use of plant stanols/sterols in forms that are sufficiently bioavailable for therapeutic effect should be a key element of maximal dietary therapy. This principle was recognized by National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and has been amply confirmed by experimental studies in humans. Since the introduction of statins, dietary therapy for control of elevated low-density lipoprotein (LDL) cholesterol levels has received less attention. The time has come, however, to reassert the importance of maximal dietary therapy as a cost-effective means for treatment of elevated LDL concentrations and for lifetime prevention of coronary heart disease.

Stanol esters decrease plasma cholesterol independently of intestinal ABC sterol transporters and Niemann-Pick C1-like 1 protein gene expression
Field, F. J., E. Born, et al. (2004), J Lipid Res 45(12): 2252-9.
Abstract: Possible mechanisms for the cholesterol-lowering effects of plant stanol esters were addressed by feeding hamsters diets containing stanol esters, cholesterol, or cholestyramine/lovastatin. ABCA1, ATP binding cassette G1 (ABCG1), ABCG5, ABCG8, and Niemann-Pick C1-like 1 (NPC1L1) mRNA levels were then estimated in duodenum, jejunum, and ileum. Plasma cholesterol was decreased by 36% and 94% in animals fed stanol esters and cholestyramine/lovastatin, respectively. Cholesterol feeding increased plasma cholesterol by 2.5-fold. Plasma plant sterols were unchanged by stanol ester feeding but became undetectable by feeding cholestyramine/lovastatin. Cholesterol and stanols accumulated in enterocytes of animals fed cholesterol and stanol esters, respectively. ABCG5 and ABCG8 mRNA levels were decreased by stanol esters and cholestyramine/lovastatin. Cholesterol feeding markedly increased ABCA1 and ABCG1 expression and modestly increased ABCG5/ABCG8. NPC1L1 mRNA was not significantly altered by any of the diets. ABCG1, ABCG5, ABCG8, and NPC1L1 mRNAs were highest in cells of the upper villus, whereas ABCA1 mRNA was highest in cells of the lower villus. The results suggest that cholesterol lowering effect of stanol esters is unrelated to changes in mRNA levels of intestinal ABC sterol transporters or NPC1L1. Cholesterol flux regulates ABC expression but not NPC1L1. The different localization of ABCA1 suggests a different function for this protein than for ABCG1, ABCG5, ABCG8, and NPC1L1.

START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells
Strauss, J. F., 3rd, T. Kishida, et al. (2003), Mol Cell Endocrinol 202(1-2): 59-65.
Abstract: The intracellular trafficking of cholesterol in steroidogenic cells plays an important role in the regulation of hormone synthesis. Recent evidence indicates that a family of proteins related to the steroidogenic acute regulatory protein (StAR) perform critical functions in moving the sterol substrate to the mitochondrial inner membrane where the first committed step in steroid hormone synthesis occurs. StAR, the prototype of the family, is known to promote the translocation of cholesterol from the outer to the inner mitochondrial membrane. Mutations in StAR cause congenital lipoid adrenal hyperplasia, a cholesterol storage disorder in which synthesis of all gonadal and adrenocortical steroid hormones is severely impaired, and the cholesterol that is not efficiently moved into the mitochondria accumulates in cytoplasmic lipid droplets. The StAR-related lipid transfer (START) domain consists of an approximately 210 amino acid residue sequence that forms a compact alpha/beta structure, a helix-grip fold, with a hydrophobic tunnel that can accommodate a sterol molecule. START domains can bind sterol, facilitate the transfer of cholesterol from sterol-rich unilammelar liposomes to acceptor membranes, and stimulate steroidogenesis when expressed in cells co-expressing the cholesterol side-chain cleavage system or when added to isolated steroidogenic mitochondria. Sixteen human START domain proteins have been identified to date. Of these, StAR and MLN64 consist of one subfamily and newly described proteins named StarD4, StarD5, and StarD6 represent a closely related second subfamily. MLN64 is incorporated into the late endosomal compartment and is involved in the movement of cholesterol acquired from endocytosed LDL out of these vesicles. Expression of a dominant negative form of MLN64 causes accumulation of free cholesterol in lysosomes. The roles of StarD4, StarD5, and StarD6 in sterol movement remain to be determined. These genes have tissue-specific patterns of expression that may predict specialized roles.

StARTing to understand cholesterol transfer
Stocco, D. M. (2000), Nat Struct Biol 7(6): 445-7.

State of the art in cholesterol management: targeting multiple pathways
Turley, S. D. (2002), Am J Manag Care 8(2 Suppl): S29-32; discussion S45-7.
Abstract: The relationship between increased serum levels of total cholesterol and increased risk of coronary heart disease (CHD) is widely accepted, as is the corollary that lowering elevated levels of low-density lipoprotein (LDL) cholesterol, a significant risk factor, reduces CHD mortality. Although statins are the most widely used agents to lower LDL cholesterol levels and demonstrate significant clinical benefits, alternate and/or additional treatment strategies are also being studied. One such approach for which several classes of agents are available is the nonspecific inhibition of intestinal cholesterol and bile acid absorption. Although all of these inhibitors-which include bile acid sequestrants, cholesterol absorption blockers, and plant stanols-reduce cholesterol concentrations within liver cells and increase the expression of LDL receptors, they are limited in their effectiveness because of poor tolerability and compensatory effects by the liver that blunt their ability to lower LDL. Ideally, the combination of a statin and another agent that specifically targets cholesterol absorption and promotes excretion while simultaneously decreasing synthesis may provide the greatest therapeutic benefit. The recent development of selective cholesterol inhibitors, including ezetimibe, provides an approach to lowering LDL that has significant potential both as monotherapy and in combination therapy.

Statin effects on cholesterol micro-domains in brain plasma membranes
Kirsch, C., G. P. Eckert, et al. (2003), Biochem Pharmacol 65(5): 843-56.
Abstract: Recent epidemiological studies revealed inhibitors of the hydroxymethylglutaryl-coenzyme A reductase, so-called statins, to be effective in lowering the prevalence of Alzheimer's disease (AD). In vitro, statins strongly reduced the cellular amyloid beta-protein load by modulating the processing of the amyloid beta precursor protein. Both observations are probably linked to cellular cholesterol homeostasis in brain. So far, little is known about brain effects of statins. Recently, we could demonstrate that treatment of mice with the lipophilic compound lovastatin resulted in a discrete reduction of brain membrane cholesterol levels. To follow up these findings, we subsequently carried out a further in vivo study including lovastatin and simvastatin as lipophilic agents, as well as pravastatin as a hydrophilic compound, focussing on their efficiency to affect subcellular membrane cholesterol pools in synaptosomal plasma membranes of mice. In contrast to the hydrophilic pravastatin, the lipophilic lovastatin and simvastatin strongly reduced the levels of free cholesterol in SPM. Interestingly, lovastatin and pravastatin but not simvastatin significantly reduced cholesterol levels in the exofacial membrane leaflet. These changes were accompanied by modified membrane bulk fluidity. All three statins reduced the expression of the raft marker protein flotillin. Alterations in transbilayer cholesterol distribution have been suggested as the underlying mechanism that forces amyloidogenic processing of APP in AD. Thus, our data give some first insight in the mode of action of statins to reduce the prevalence of AD in clinical trials.

Statin inhibition of Fc receptor-mediated phagocytosis by macrophages is modulated by cell activation and cholesterol
Loike, J. D., D. Y. Shabtai, et al. (2004), Arterioscler Thromb Vasc Biol 24(11): 2051-6.
Abstract: OBJECTIVES: An inflammatory response to altered lipoproteins that accumulate in the arterial wall is a major component of the pathogenesis of atherosclerosis. Statins reduce plasma levels of low-density lipoprotein (LDL) and are effective treatments for atherosclerosis. It is hypothesized that they also modulate inflammation. The aim of this study was to examine whether lovastatin inhibits macrophage inflammatory processes and clarify its mechanism of action. METHODS AND RESULTS: We examined the effects of statins on phagocytosis of antibody-coated red blood cells by cultured human monocytes and mouse peritoneal macrophages. Lovastatin, simvastatin, and zaragozic acid, a squalene synthase inhibitor, blocked Fc receptor-mediated phagocytosis by cultured human monocytes and mouse peritoneal macrophages. The inhibitory effect of lovastatin on Fc receptor-mediated phagocytosis was prevented completely by addition of mevalonate, farnesyl pyrophosphate, LDL, or cholesterol to the culture medium. The inhibitory effect of zaragozic acid was reversed by addition of LDL, but not by the addition of geranylgeranyl pyrophosphate, to the medium. In addition, the effect of lovastatin on phagocytosis is a function of cell activation because treatment of cells with tumor necrosis factor-alpha or lipopolysaccharide prevented inhibition of phagocytosis by lovastatin. CONCLUSIONS: The inhibition of Fc receptor-mediated phagocytosis of lovastatin is related to its effect on cholesterol biosynthesis rather than its effect on the formation of isoprenoids.

Statin is indicated to all patients with high risk of complications of coronary heart disease irrespective of the level of low density lipoprotein cholesterol. Results of HPS
Gratsianskii, N. A. (2002), Kardiologiia 42(2): 84-5.

Statin therapy and reductions in low-density lipoprotein cholesterol: initial clinical data on the potent new statin Rosuvastatin
Olsson, A. G. (2001), Am J Cardiol 87(5A): 33B-36B.
Abstract: The utility of statins with increased potency in reducing low-density lipoprotein cholesterol (LDL-C) is indicated by evidence that aggressive LDL-C lowering is associated with increased reduction in coronary artery disease risk, and the need for such agents is illustrated by the fact that many patients currently fail to achieve LDL-C target levels during treatment with available drugs. In dose-ranging studies of patients with hypercholesterolemia, the new synthetic statin rosuvastatin (formerly ZD4522) produced significant, dose-dependent reductions in LDL-C compared with placebo across a range of doses. Reductions ranged from 34% at 1 mg per day to 65% at 80 mg per day, with linear regression analysis indicating an additional 4.5% reduction in LDL-C with each doubling of the rosuvastatin dose. Rosuvastatin treatment was well tolerated. Phase 3 clinical trials of this agent are under way.

Statin therapy for prevention of coronary artery disease with average cholesterol levels
Gambhir, D. S. (1999), Indian Heart J 51(1): 19-20, 105.

Statin therapy has no significant effect on skin tissue cholesterol: results from a prospective randomized trial
Reiter, M., S. Wirth, et al. (2005), Clin Chem 51(1): 252-4.

Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease
Nissen, S. E., E. M. Tuzcu, et al. (2005), N Engl J Med 352(1): 29-38.
Abstract: BACKGROUND: Recent trials have demonstrated better outcomes with intensive than with moderate statin treatment. Intensive treatment produced greater reductions in both low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP), suggesting a relationship between these two biomarkers and disease progression. METHODS: We performed intravascular ultrasonography in 502 patients with angiographically documented coronary disease. Patients were randomly assigned to receive moderate treatment (40 mg of pravastatin orally per day) or intensive treatment (80 mg of atorvastatin orally per day). Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis. Lipoprotein and CRP levels were measured at baseline and follow-up. RESULTS: In the group as a whole, the mean LDL cholesterol level was reduced from 150.2 mg per deciliter (3.88 mmol per liter) at baseline to 94.5 mg per deciliter (2.44 mmol per liter) at 18 months (P<0.001), and the geometric mean CRP level decreased from 2.9 to 2.3 mg per liter (P<0.001). The correlation between the reduction in LDL cholesterol levels and that in CRP levels was weak but significant in the group as a whole (r=0.13, P=0.005), but not in either treatment group alone. In univariate analyses, the percent change in the levels of LDL cholesterol, CRP, apolipoprotein B-100, and non-high-density lipoprotein cholesterol were related to the rate of progression of atherosclerosis. After adjustment for the reduction in these lipid levels, the decrease in CRP levels was independently and significantly correlated with the rate of progression. Patients with reductions in both LDL cholesterol and CRP that were greater than the median had significantly slower rates of progression than patients with reductions in both biomarkers that were less than the median (P=0.001). CONCLUSIONS: For patients with coronary artery disease, the reduced rate of progression of atherosclerosis associated with intensive statin treatment, as compared with moderate statin treatment, is significantly related to greater reductions in the levels of both atherogenic lipoproteins and CRP.

Statin trials and goals of cholesterol-lowering therapy
Grundy, S. M. (1998), Circulation 97(15): 1436-9.

Statin trials and goals of cholesterol-lowering therapy after AMI
Pedersen, T. R. (1999), Am Heart J 138(2 Pt 2): S177-82.
Abstract: Several randomized clinical trials using statins in the prevention of coronary heart disease (CHD) have demonstrated benefit, both in terms of retardation of the progression of signs of coronary atherosclerosis and in reduced morbidity and mortality rates. Three of these trials have examined the long-term effect of statins in patients with previous myocardial infarction. The Scandinavian Simvastatin Survival Study (4S) showed that a mean reduction of low-density-lipoprotein (LDL) cholesterol by 35% reduced coronary mortality rates by 42% and total mortality rates by 30%. In the Cholesterol and Recurrent Events trial, a 28% reduction in LDL-cholesterol was associated with a reduction in major coronary events of 24%. In the Long Term Intervention with Pravastatin in Ischemic Disease study, the 25% LDL-cholesterol reduction produced a 24% reduction in coronary disease mortality rates and 22% reduction in death from all causes. All event reductions were highly statistically significant. Other trials using statins in patients without signs of CHD have yielded similar risk reductions. Post hoc analysis of the results of the trials have produced diverging indications as to what is the optimal goal of cholesterol lowering. Analysis of the 4S indicates that aggressive treatment aiming at LDL-cholesterol levels lower than the current recommendations of expert panels in the United States and in Europe may yield additional benefit. This strategy finds some support in epidemiological studies and in a study with angiographic end points. Analysis of two trials using pravastatin contradict this and conclude that there is little or no additional benefit of reducing LDL-cholesterol below 125 mg/dL (3.2 mmol/L). Future studies need to address this question prospectively.

Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy
Lima, J. A., M. Y. Desai, et al. (2004), Circulation 110(16): 2336-41.
Abstract: BACKGROUND: Statin therapy reduces adverse outcomes, with a minimal decrease in vessel stenosis. Magnetic resonance imaging (MRI) noninvasively detects atherosclerotic plaque (AP) reduction. We hypothesized that statin-induced AP regression can be monitored by MRI and detected earlier than previously reported and is significantly associated with its lipid-lowering effect. METHODS AND RESULTS: APs in thoracic aorta were measured by combined surface/transesophageal MRI in 27 patients (treated with simvastatin 20 to 80 mg daily) before and after 6 months of therapy. AP volume and luminal dimensions were measured from 6 cross sections used to construct a 2.4-cm 3D volume of the aorta that included plaque and lumen. Method reproducibility was studied in 10 patients imaged twice, 1 week apart. AP volume was reduced from 3.3+/-0.1.4 to 2.9+/-1.4 cm3 at 6 months (P<0.02), whereas luminal volume increase was less accentuated (from 12.0+/-3.9 to 12.2+/-3.7 cm3, P<0.06). LDL cholesterol decreased by 23% (from 125+/-32 to 97+/-27 mg/dL, P<0.05) in 6 months. AP regression (plaque volume/area reduction) was significantly related to LDL cholesterol reduction (P<0.02 and P<0.005, respectively), and luminal volume increase was inversely related to LDL cholesterol reduction (P<0.04). Plaque volume measurement was highly reproducible (intraclass correlation R=0.98 and variability=4.8%). Intraobserver (0.91) and interobserver (0.81) concordances were documented for plaque volume assessment. CONCLUSIONS: AP regression and reverse remodeling can be detected accurately by MRI 6 months after statin therapy initiation, and it is strongly associated with LDL cholesterol reduction.

Statins (HMG-CoA reductase inhibitors), cholesterol and stroke
Marta-Moreno, J., C. Echeandia, et al. (1998), Rev Neurol 27(159): 827-30.
Abstract: The HMG-CoA reductase inhibitors (known as statins) have been shown to reduce morbi-mortality of vascular origin, including transitory ischemic accidents and cerebral infarcts, in a large group of patients. The implications, both clinical and of costs, oblige us to consider analysis of the existing evidence and the answers to a number of questions arising in a field which has not yet received much attention from neurologists.

Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing microdomains
Kuipers, H. F., P. J. Biesta, et al. (2005), Hum Immunol 66(6): 653-65.
Abstract: Statins, the main therapy for hypercholesterolemia, are currently considered as possible immunomodulatory agents. Statins inhibit the production of proinflammatory cytokines and reduce the expression of several immunoregulatory molecules, including major histocompatibility complex class II (MHC-II) molecules. In this study, we investigated the mechanism by which simvastatin reduces the membrane expression of MHC-II molecules on several human cell types. We demonstrate that the reduction of MHC-II membrane expression by simvastatin correlates with disruption of cholesterol-containing microdomains, which transport and concentrate MHC-II molecules to the cell surface. In addition, we demonstrate that statins reduce cell-surface expression of other immunoregulatory molecules, which include MHC-I, CD3, CD4, CD8, CD28, CD40, CD80, CD86, and CD54. Our observations indicate that the downregulation of MHC-II at the cell surface contributes to the immunomodulatory properties of statins and is achieved through disruption of cholesterol-containing microdomains, which are involved in their intracellular transport.

Statins and exercise-induced myocardial ischemia. From vascular pleiotropic effects to the importance of reducing LDL-cholesterol
Marques da Silva, P. (2004), Rev Port Cardiol 23(9): 1109-14.

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