The Impact of Simvastatin on Lipidomic Markers of Cardiovascular Risk in Human Liver Cells Is Secondary to the Modulation of Intracellular Cholesterol (original) (raw)
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Lipids in Health and Disease, 2011
Background: Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/-mice fed a high-fat diet. Results: The atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/-mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoproteincholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups.
Journal of Clinical Biochemistry and Nutrition, 1995
The effects of simvastatin, a cholesterol biosynthesis inhibitor, on plasma lipoprotein concentrations and very-low-density lipoprotein (VLDL) secretion were investigated in the rat. The results showed that simvastatin did not significantly modify plasma lipid levels but did increase the cholesterol level of apolipoprotein E-rich high-density lipoproteins (+ 31%). The treatment significantly reduced total VLDL secretion (-26%), assessed by VLDL-triacylglycerol accumulation in plasma after lipolysis inhibition by Triton WR 1379. Since intestinal VLDL production, which was measured in rats fed orotic acid in order to block the hepatic secretion of lipoproteins, was not changed, we deduced that simvastatin reduced by 50% the hepatic VLDL secretion. Furthermore, whole-body cholesterol production, assessed by the sterol balance, appeared inhibited in the rat after long-term simvastatin treatment.
Metabolism, 1992
This multicenter, double-blind, randomized study was designed to compare the effects of simvastatin (20 mg/d and 40 mg/d) and fenofibrate (400 mg/d) on plasma lipids, lipoproteins, apolipoproteins (apo), and lipoprotein particles defined by their apo composition (Lp A-l, Lp A-II:A-I, Lp E:B, Lp C-III:B) in primary hypercholesterolemia. After 6 and 10 weeks of therapy, both drugs lowered plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apo B. The effect on LDL and apo B was significantly more pronounced for simvastatin (P = .Ol). Simvastatin increased Lp A-l, but did not change Lp A-II:A-I, while fenofibrate decreased Lp A-l and increased Lp A-II:A-I. Lp E:B and Lp C-III:B were decreased with both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin. This study demonstrates that both drugs have beneficial effects on the parameters positively or negatively correlated with the atherosclerotic risk, with simvastatin being more effective in reducing some of them. These results suggest that the drugs led to different structural modifications of the lipoproteins, which would not be revealed by examination of lipoprotein density classes. These differences are probably related to the different mechanisms of action of the agents.
Diabetologia, 2005
Aim/hypothesis Cellular cholesterol effl ux to plasma is important in reverse cholesterol transport and may be aff ected by simvastatin in type 1 diabetes mellitus. Methods In 14 moderately hypercholesterolaemic type 1 diabetic and 13 healthy men we determined plasma (apo)lipoproteins, pre β-HDL formation, cholesteryl ester transfer protein (CETP) activity, phospholipid transfer protein (PLTP) activity, cholesterol esterifi cation (EST), cholesteryl ester transfer (CET) and the capacity of plasma to induce cholesterol effl ux out of Fu5AH cells and fi broblasts. After diet run-in, diabetic patients were randomly treated with simvastatin 10 mg, 20 mg, 40 mg and placebo once daily each during six weeks in a double blind cross-over design. Results Plasma VLDL+LDL cholesterol, LDL cholesterol, HDL phospholipids, apo A-I, apo B, CETP activity, PLTP activity, EST, CET and the capacity of plasma to induce cholesterol effl ux from Fu5AH cells and fi broblasts were higher in diabetic patients. Pre β-HDL formation was unaltered. Simvastatin treatment decreased VLDL+LDL cholesterol, LDL cholesterol, TG and apo B, CETP activity, EST and CET. HDL cholesterol increased and its change was correlated with the change in CET. Th e ability to promote cholesterol effl ux from Fu5AH cells and fi broblasts did not change after simvastatin. Conclusion/interpretation Th e capacity of plasma from moderately hypercholesterolaemic type 1 diabetic patients to induce cholesterol effl ux out of Fu5AH cells and fi broblasts is enhanced, probably due to higher apo A-I, HDL phospholipids and PLTP activity. Simvastatin increases HDL cholesterol in type 1 diabetic patients via lowering of plasma CET. Th e HDL changes after simvastatin do not further increase cellular cholesterol effl ux.
Acta Biochimica Polonica, 2013
The statin-induced effects on high density lipoprotein (HDL) are relatively small compared with those of low density lipoprotein (LDL) and, as a result, most clinical trials of statins are underpowered with respect to HDL parameters. This study experimentally investigated, the effects of statin on serum lipids, atherogenic index and examined the possibility of a relationship amongst serum concentrations of HDL-C, atherogenic index and activity of lecithin:cholesterol acyl transferase. Method: Thirty albino rats equally divided into 2 groups were used for the study. Group 1 was given 0.05mg/g of statin daily for 28 days, while group 2 served as control. HDL concentration was determined as a measure of HDL-C. Total cholesterol (TC), triglyceride (TG) and HDL-C were determined spectrophotometrically while LDL-C was calculated using the Frieldwald formula. Effect on the activity of lecithin:cholesterol acyl transferase was determined by the difference between the amount of free cholesterol converted to cholesteryl ester in the two experimental groups. Effects on body and relative organs weights were also determined. Results: The administration of statin caused a significant increase in serum concentration of HDL-C, while levels of LDL-C, triglyceride and total cholesterol were reduced. Simvastatin caused a significant reduction in the atherogenic index (TC/HDL-C; LDLC/HDL-C). The administration of statin significantly induced the activity of lecithin:cholesterol acyl transferase (LCAT) as evident by reduced serum concentration of free cholesterol when compared with control. The administration of statin caused reduced body and relative organs weights. Conclusion: The study showed that serum antihyperlipidemic and antiatherogenic activity of statin may involve the induction of LCAT.
Atherosclerosis, 2000
The short-and long-term in vitro effects of the hydroxymethylglutaryl-CoA reductase inhibitor atorvastatin, compared with lovastatin and simvastatin on VLDL secretion, and on the formation and the neutral and acid lysosomal hydrolysis of cholesteryl esters was investigated in rat liver hepatocytes maintained in suspension (2 or 4 h) or cultured in monolayers (24 h). All statins time-dependently reduced [ 14 C]oleate incorporation into cholesteryl esters, but when exogenous cholesterol was added only atorvastatin caused an immediate transient decrease in hepatocyte ACAT activity. Activity of the lysosomal, microsomal and cytosolic CEH isoforms was unaffected by the hepatocyte treatments. Statins reduced free and esterified cholesterol mass in hepatocyte microsomes after 2 h, and this was followed by a modest decline in VLDL cholesteryl esters, whilst secretion of VLDL apoB and triglycerides was unaltered. However, after 24 h of treatment, statins caused generalized 20 -40% decreases in the secretion of VLDL apoB, cholesterol and triglycerides, with the reduction in apoB48 secretion being significantly superior to that caused in apoB100. The mean diameter of secreted VLDL was not modified by either duration or drug treatment. Additional studies with subcellular fractions demonstrated that statins have a direct selective effect on the enzymes governing the cholesterol-cholesteryl ester cycle, with the exception of the microsomal CEH. Atorvastatin, lovastatin and simvastatin inhibited ACAT activity in microsomes by 50% at doses of 250, 100 and 50 mM, respectively. The cytosolic CEH elicited a biphasic profile of activity with activations up to 100 mM statin and inhibitions above 250 mM, and the lysosomal CEH was only inhibited by atorvastatin at a dose of 100 mM or more. We conclude that a prolonged, but not a short, limited availability of hepatocyte cholesterol derived from the endogenous synthesis reduces VLDL secretion, and that reactivity of statins at the cellular level are more similar than reactivity at the subcellular level as regards the cholesterol-cholesteryl ester cycle.
Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients
Atherosclerosis, 2009
Background-Lipophilic and hydrophilic statins have different effects on adiponectin and insulin resistance in experimental studies and different effects on the rate of onset of new diabetes in large scale clinical studies. Therefore, we hypothesized that simvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients.
Metabolomics, 2010
Statins are commonly used for reducing cardiovascular disease risk but therapeutic benefit and reductions in levels of low-density lipoprotein cholesterol (LDL-C) vary among individuals. Other effects, including reductions in C-reactive protein (CRP), also contribute to treatment response. Metabolomics provides powerful tools to map pathways implicated in variation in response to statin treatment. This could lead to mechanistic hypotheses that provide insight into the underlying basis for individual variation in drug response. Using a targeted lipidomics platform, we defined lipid changes in blood samples from the upper and lower tails of the LDL-C response distribution in the Cholesterol and Pharmacogenetics study. Metabolic changes in responders are more comprehensive than those seen in non-responders. Baseline cholesterol ester and phospholipid metabolites correlated with LDL-C response to treatment. CRP response to therapy correlated with baseline plasmalogens, lipids involved in inflammation. There was no overlap of lipids whose changes correlated with LDL-C or CRP responses to simvastatin suggesting that distinct metabolic pathways govern statin effects on these two biomarkers. Metabolic signatures could provide insights about variability in response and mechanisms of action of statins.
Canadian Journal of Physiology and Pharmacology, 2003
Since hypercholesterolemia directly modifies the composition of erythrocytes plasma membrane, the influence of statins on erythrocytes has been researched. The beneficial effects of statins on clinical events may involve mechanisms that modify endothelial dysfunction, plaque stability, thrombus formation and inflammatory responses. The aim of the study was to evaluate the hypolipemic efficacy and effects of pravastatin and simvastatin on erythrocyte membrane fluidity and damage of erythrocytes in patients with type 2 hypercholesterolemia in comparison with a control group of healthy subjects. The study involved 53 patients affected by type 2 hypercholesterolemia (mean age, 53.3 ± 10.3) with initial total serum cholesterol (TC) levels > 250 mg/dL, LDL-cholesterol (LDL-C) levels > 170 mg/dL, and triglycerides (TG) levels < 400 mg/dL. The control group consisted of 30 healthy individuals (mean age 56.9 ± 6.3). Statins were given for 12 weeks. The dosages for oral administration of simvastatin and pravastatin were 20 mg/day. Laboratory tests were carried out before and after 4 and 12 weeks of the pharmacological treatment. The damage to plasma membrane of erythrocytes was measured on the basis of lipid peroxidation. The fluidity of plasma membrane of erythrocytes was determined by electron paramagnetic resonance (EPR) spectroscopy, using two spin labels: 5-DSA and 16-DSA. The cholesterol level in the membrane of red blood cells was estimated. Simvastatin and pravastatin reduced the total cholesterol concentration and LDL-cholesterol in plasma, as well as the cholesterol concentration in erythrocytes membranes. Hypercholesterolemia induced changes in the basic properties of human erythrocyte plasma membrane, including its fluidity and the intensity of lipid peroxidation. These results indicate that the simvastatin and pravastatin therapy reverses the alteration in the erythrocyte plasma membrane properties.
Atherosclerosis, 2002
Clinical studies have recently suggested that statin treatment may beneficially elevate plasma concentrations of high density lipoprotein (HDL)-cholesterol in patients with hyperlipidemia. Here, we have investigated the effect of a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on the synthesis and secretion of apolipoprotein AI (apoAI) in two model systems, HepG2 cells and primary hamster hepatocytes. Cultured cells were incubated with different doses of simvastatin (0.1-10 microM) for a period of 18 h. A dose-dependent increase in synthesis and secretion of apoAI was observed in both cell types. There was a significant increase in the synthesis of apoAI in HepG2 cells (44.3+/-12.1%), and hamster hepatocytes (212+/-2%) after treatment with 10 microM of the statin. The increase in apoAI synthesis appeared to result in a higher level of apoAI secreted into the culture media in both cell types (49.2+/-7.8% in HepG2, 197+/-0.2% in hamster hepatocytes). ApoAI mRNA levels were also significantly increased in both cell types in response to statin treatment. Control experiments with transferrin confirmed specificity of the effect on apoAI secretion. Analysis of a density fraction containing HDL particles in culture media revealed an increase in HDL-associated apoAI of 94.3+/-2.1% in HepG2 cells and 27.0+/-0.03% in hamster hepatocytes following 10 microM simvastatin-treatment. Comparative studies of simvastatin and lovastatin indicated a differential ability to induce apoAI synthesis and secretion, with simvastatin having a more significant effect. Thus, acute statin treatment of cultured hepatocytes (transformed as well as primary) resulted in a significant upregulation of apoAI mRNA and apoAI synthesis, causing oversecretion of apoAI and HDL extracellularly. The stimulatory effect on apoAI synthesis and secretion may thus explain the clinical observation of an elevated plasma HDL-cholesterol level in hyperlipidemic patients treated with certain statins.