Academic literature on the topic 'Cholesterol Physiological effect'

The present study was undertaken to search out thebeneficial effect of magnetized water on serumantioxidant, lipid profile and total protein of adult male rabbits. Twenty adult male rabbits were randomly divided into two equal groups and were treated daily for 60 days as follows:Group C:Rabbits of this group were allowed to ad libitumsupplyofdrinking water (control group),Group MG:Rabbits of this group were allowed to ad libitum supply of magnetic water.Fasting blood (for 8-12 hrs) samples were drawn by cardiac puncture technique at different times 0, 30 and 60 days of experiment for measuring the following parameters. Serum glutathione concentration (GSH), lipid profile including serum triacylglycerol (TAG), total cholesterol - (TC), high density lipoprotein - cholesterol (HDL-C), low density lipoprotein - cholesterol (LDL-C) and very low density lipoprotein cholesterol - (VLDL-C), total serum protein concentrations (TSP). The result revealed that drinking of magnetic water had beneficial effect on some physiological aspects manifested by a significant elevation in serum GSH, HDL-C and total serum proteins concentration. In addition to significant suppression in serums TC, TAG, LDL-C, and VLDL-C concentrations .In conclusion the results of this study pointed to the prevalence of magnetic water upon normal drinking water in all measures issued.

Background: Several various physiological functions in elderly people are diminished due to cell or tissue damage. One of the probable causes are oxidative stress yielded by free radicals.Oxidative stress (ROS) induce lipid peroxidation in endothelial cell membrane, which generates atherosclerotic plaque. In a state of oxidative stress, MDA level will increased. The purpose of this study is to determine the effect of SOD supplementation on MDA, total cholesterol and LDL cholesterol plasma levels in the elderly.Methods: This study was open label, a randomized control trial. Subjects were elderly people aged > 60 years (median 75, 60-82 ys, male 10 (24,4%)) institutionalized at Social Rehabilitation Unit Pucang Gading Semarang, Indonesia. The treatment group consisted of 16 people, received SOD (GlisodinR) 1 capsule (250 IU) 1 hour before meals, plus exercise scheduled for 8 weeks. The control group consisted of 15 people, received placebo, and exercise. Plasma MDA levels were examined using TBARS method, while total cholesterol and LDL cholesterol were examined using CHOD-PAP method.Results: This study show a reduction of plasma MDA levels in the treatment group compare to control group ( p = 0.062 ). A significant reduction of total cholesterol and LDL cholesterol levels in the treatment group were found (before 190.00 and 131.47 g/dl, after 182.27 and 121.93 g/dl, p = 0.005 and 0.001).Conclusion: The SOD supplementation significantly reduce Total Cholesterol and LDL level, but not MDA level in the elderly.

1. Cholesteryl ester transfer protein activity may have a physiological effect on high-density lipoprotein levels. 2. We examined restriction fragment length polymorphisms associated with the cholesteryl ester transfer protein gene and the apolipoprotein AI gene in a group of 60 unrelated subjects selected from an initial survey of 5000 subjects on the basis of their high-density lipoprotein levels being high or low at the extremes of the distribution. The activities of cholesteryl ester transfer protein and lectithin:cholesterol acyltransferase (phosphatidylcholine-sterol acyltransferase, EC 2.3.1.43) were also determined. Analysis by selection of those with a low high-density lipoprotein cholesterol level (≤ 1.1 for males, ≤ 1.2 for females) gave 32 individuals with 24% B2 alleles. Selection of subjects with a high-density lipoprotein cholesterol level (≥ 2 mmol/l) gave 17 with 62% B2 alleles. 3. The group with low levels of high-density lipoprotein cholesterol had higher activity of cholesteryl ester transfer protein and significantly elevated triacylglycerol levels when compared with the group with high levels of high-density lipoprotein cholesterol. 4. A further significant finding was the correlation of the Msp1 restriction fragment length polymorphism detected by the apolipoprotein AI gene with lecithin:cholesterol acyltransferase activity.

<p class="abstract"><strong>Background:</strong> The association of cholecystectomy with alterations in lipid profile is well documented. Objectives of this study were to determine the effect of cholecystectomy on lipid profile of cholelithiasis patients.</p><p class="abstract"><strong>Methods:</strong> This cross-sectional observational study was done on 170 patients admitted in general surgery department of Naz Memorial Hospital, Karachi from July 2018 to June 2019. Symptomatic cholelithaisis patients between 18 to 60 years, elective cholecystectomy was included while patients previously on lipid lowering agents, diagnosed renal failure, nephrotic syndrome, cardiac failure, pregnant mothers, hypothyroidism, pancreatitis and obstructive jaundice were excluded. For data analysis, SPSS was used. Wilcoxon signed ranked test was used to compare mean values of pre and post-operative lipid profiles after cholecystectomy keeping p value of &lt;0.05 as significant. </p><p class="abstract"><strong>Results:</strong> 60% of patients were females with majority, 31% patients between 31-40 years while least, i.e. 11% were between 61-70 years. The mean pre-operative and post-operative difference of 52±7.32 mg/dl was seen in total cholesterol levels (p&lt;0.001). The mean difference in high density lipoprotein (HDL) between pre and post-operative was of 13±0.36 mg/dl (p&lt;0.001). The mean difference in low density lipoprotein (LDL) between pre- and post-operative was 61±10.45 mg/dl (p&lt;0.001). The mean difference in triglycerides levels between pre- and post-operative was 46±25.49 mg/dl (p&lt;0.001).</p><p class="abstract"><strong>Conclusions:</strong> Cholecystectomy in gall stone disease patients elicited favorable response in significantly lowering levels of total serum cholesterol, LDL and triglycerides while substantially increasing levels of HDL cholesterol.</p><p> </p>

Cholesterol is responsible for the plasticity of plasma membranes and is involved in physiological and pathophysiological responses. Cholesterol homeostasis is regulated by oxysterols, such as 25-hydroxycholesterol. The presence of 25-hydroxycholesterol at the membrane level has been shown to interfere with several viruses’ entry into their target cells. We used atomic force microscopy to assess the effect of 25-hydroxycholesterol on different properties of supported lipid bilayers with controlled lipid compositions. In particular, we showed that 25-hydroxycholesterol inhibits the lipid-condensing effects of cholesterol, rendering the bilayers less rigid. This study indicates that the inclusion of 25-hydroxycholesterol in plasma membranes or the conversion of part of their cholesterol content into 25-hydroxycholesterol leads to morphological alterations of the sphingomyelin (SM)-enriched domains and promotes lipid packing inhomogeneities. These changes culminate in membrane stiffness variations.

AbstractCVD affect a large proportion of the world’s population, with dyslipidaemia as the major risk factor. The regular consumption of both probiotic bacteria and yeast has been associated with improvement in the serum lipid profile. Thus, the present review aims to describe and discuss the potential mechanisms responsible for the hypocholesterolaemic effect of regular consumption of probiotic bacteria and yeast. Regarding the hypocholesterolaemic effect of probiotic bacteria, the potential mechanisms responsible include: deconjugation of bile salts; modulation of lipid metabolism; and decreased absorption of intestinal cholesterol through co-precipitation of intestinal cholesterol with the deconjugated bile salts, incorporation and assimilation of cholesterol in the cell membrane of the probiotics, intestinal conversion of cholesterol in coprostanol, and inhibition of the expression of the intestinal cholesterol transporter Niemann–Pick C1 like 1 (NPC1L1) in the enterocytes. The potential mechanisms responsible for the hypocholesterolaemic effect of probiotic yeasts include: deconjugation of bile salts; co-precipitation of intestinal cholesterol with the deconjugated bile salts; incorporation and assimilation of cholesterol in the cell membrane; and inhibition of hepatic cholesterol synthesis. The regular consumption of probiotic bacteria and yeast, as a non-pharmaceutical approach to help manage cardiovascular risk, holds promise, according to the beneficial hypocholesterolaemic effects described herein. However, the hypocholesterolaemic effects vary according to the strains used, the physiological state of the host, and the type of diet to which the probiotics are added. Further studies are necessary to fill the gaps with regard to the knowledge related to this topic.

Lipoproteins may supply substrate for the formation of bile acids, and the amount of hepatic cholesterol can regulate bile-acid synthesis and increase cholesterol 7α-hydroxylase expression. However, the effect of lipoprotein cholesterol on sterol 27-hydroxylase expression and the role of different lipoproteins in regulating both enzymes are not well established. We studied the effect of different rabbit lipoproteins on cholesterol 7α-hydroxylase and sterol 27-hydroxylase in cultured rat hepatocytes. β-Migrating very-low-density lipoprotein (βVLDL) and intermediate-density lipoprotein (IDL) caused a significant increase in the intracellular cholesteryl ester content of cells (2.3- and 2-fold, respectively) at a concentration of 200 μg of cholesterol/ml, whereas high-density lipoprotein (HDL, 50% v/v), containing no apolipoprotein E (apo E), showed no effect after a 24-h incubation. βVLDL and IDL increased bile-acid synthesis (1.9- and 1.6-fold, respectively) by up-regulation of cholesterol 7α-hydroxylase activity (1.7- and 1.5-fold, respectively). Dose- and time-dependent changes in cholesterol 7α-hydroxylase mRNA levels and gene expression underlie the increase in enzyme activity. Incubation of cells with HDL showed no effect. Sterol 27-hydroxylase gene expression was not affected by any of the lipoproteins added. Transient-expression experiments in hepatocytes, transfected with a promoter-reporter construct containing the proximal 348 nucleotides of the rat cholesterol 7α-hydroxylase promoter, showed an enhanced gene transcription (2-fold) with βVLDL, indicating that a sequence important for a cholesterol-induced transcriptional response is located in this part of the cholesterol 7α-hydroxylase gene. The extent of stimulation of cholesterol 7α-hydroxylase is associated with the apo E content of the lipoprotein particle, which is important in the uptake of lipoprotein cholesterol. We conclude that physiological concentrations of cholesterol in apo E-containing lipoproteins increase bile-acid synthesis by stimulating cholesterol 7α-hydroxylase gene transcription, whereas HDL has no effect and sterol 27-hydroxylase is not affected.

Sterol carrier protein2 (SCP2) is known to stimulate utilization of cholesterol in enzymic reactions in which cholesterol is the substrate. Substantial recent experimental evidence indicates that SCP2: activates enzymic conversion of intermediates between lanosterol and cholesterol; stimulates the microsomal conversion of cholesterol into cholesterol ester in rat liver; and enhances mitochondrial utilization of cholesterol for pregnenolone formation in the adrenals. The conversion of cholesterol into 7 α-hydroxycholesterol is the rate-limiting step in bile-acid synthesis. We therefore investigated the effect of SCP2 on this physiologically critical reaction by using a gas-chromatography-mass-spectrometry procedure that measures the mass of 7 α-hydroxycholesterol formed. The results show that SCP2 enhances 7 α-hydroxycholesterol formation by rat liver microsomes (microsomal fractions), utilizing either endogenous membrane cholesterol, cholesterol supplied exogenously in serum or in the form of cholesterol/phospholipid liposomes. Microsomes immunotitrated with anti-SCP2 antibody exhibited considerably less capacity to synthesize 7 α-hydroxycholesterol, which was restored to control levels on addition of purified SCP2. These data are consistent with the suggestion that SCP2 may be of physiological significance in the overall metabolism of cholesterol.

Human aortic extracts contain significant cholesteryl ester hydrolytic activity. The enzymic activity was shown to be activated by trihydroxylated bile salt, but not by dihydroxylated bile salt. Monospecific antibodies prepared against rat pancreatic carboxyl ester lipase (CEL, cholesterol esterase) immunoprecipitated cholesteryl ester hydrolytic activity from human aorta, demonstrating that the neutral CEL in aorta is highly similar to and probably identical with the pancreatic enzyme. Reverse transcriptase PCR amplification of mRNA from human aortic endothelial cells revealed de novo synthesis of the pancreatic-type CEL by these cells. Preincubating human aortic endothelial cells with oxidized or native low-density lipoprotein resulted in an 8- and 3-fold increase in CEL activity secreted into the culture medium respectively. A potential physiological role for the endothelial CEL was demonstrated by studies showing its ability to confer partial protection against the cytotoxic effects of lysophosphatidylcholine. The protective effect of CEL is related to its bile-salt-independent lysophospholipase activity. However, CEL hydrolysis of lysophosphatidylcholine can be inhibited by excess cholesterol. Taken together, these results indicate that pancreatic-type CEL is synthesized by cells lining the vessel wall. Moreover, vascular CEL may interact with cholesterol and oxidized lipoproteins to modulate the progression of atherosclerosis.

The short-term effects of whole milk and milk fermented by Pseudomonas fluorescens, of the amino acid composition of the diet and of feeding frequency on the level of plasma lipids, were investigated in six 1-year-old adult boars. The experimental diets contained equal amounts of protein, carbohydrates, fat and cholesterol. After an adaptation period of 5 d for each experimental treatment, blood was collected at regular intervals during 48 h and plasma levels of cholesterol, triacylglycerol, high-density-lipoprotein (HDL)-cholesterol and low-density-lipoprotein (LDL-cholesterol were examined). All variables except HDL-cholesterol showed distinct diurnal fluctuations, which were substantially influenced by feeding frequency. Variations in the amino acid composition of the experimental diets, which were within a physiological range, had no effect on the level of plasma lipids. Plasma lipid levels were significantly lower when the animals received the diets containing milk instead of the diet without milk: cholesterol, triacylglycerol, and LDL-cholesterol were reduced by 5.6, 5.8 and 10% respectively (pondered means) while HDL-cholesterol remained unaffected. Fermentation of whole milk by P. fluorescens reduced the lipid-lowering effect. Our findings suggest that the intake of diets containing milk results in a lower plasma cholesterol and LDL-cholesterol level than the intake of diets with a similar nutrient content which do not contain milk.

Statins are widely used to treat hypercholesterolemia. Statins inhibit cholesterol biosynthesis, thereby activating genes involved in cholesterol homeostasis, which are under the control of the Sterol Regulatory Element (SRE). Statins also have cholesterol-independent beneficial cardiovascular effects mediated through the phosphoinositide 3-kinase (PI3-K) / Akt signaling pathway and by inhibition of protein prenylation. Because statins inhibit the synthesis of isoprenoids, they can act by inhibiting the small signaling GTPases Ras and Rho, which require post-translational prenylation to become membrane-anchored and functional. We showed that simvastatin-mediated inhibition of protein prenylation does not appear to play a role in activation of SRE transcriptional activity in HepG2 cells. We also found that when isoprenoids were replenished, basal phospho-Akt decreased, suggesting that inhibition of prenylation by simvastatin mediates Akt phosphorylation. Future studies will be needed to investigate the role that inhibition of protein prenylation plays in the activation of the PI3-K/Akt pathway by simvastatin.
Department of Biology

The cholesterol-lowering effect of corn fiber oil, obtained from the seed coats of corn kernels, has been reported previously. Corn fiber oil contains phytosteryl fatty acyl esters, ferulate phytostanyl esters, and free phytosterols. To date, however, no studies have examined the cholesterol-lowering efficacy of ferulate phytostanyl esters. Moreover, although plant stanols and sterols have been established as cholesterol-lowering agents over the past five decades, their exact mechanisms of action are not clearly understood. One of the possible mechanism is that plant sterols/stanols disrupts the normal sub-cellular cholesterol absorption by down-regulation of the influx sterol transporters such as the Niemann pick C1 like 1(NPC1L1) protein and/or up-regulation of efflux sterol transporters such as the ATP binding cassette (ABC) G5 and ABCG8 protein. Hence, the objectives of this thesis were to assess the efficacy of corn fiber oil, ferulate phytostanyl esters and their parent compounds including sitostanol and ferulic acid, on plasma cholesterol levels. Further, objectives were to investigate their impact on parameters of cholesterol kinetics and gene expression of sterol transporters to obtain insight into their role in genetic control of regulation of cholesterol flux. Results of this experiment demonstrate that the hypocholesterolemic effect of corn fiber oil is mostly due to sitostanol, while esterification of ferulic acid and sitostanol yields no apparent synergistic cholesterol lowering effect. Present data exhibited a cholesterol absorption lowering effect of corn fiber oil and sitostanol and suggest that this effect may be due to up-regulation of intestinal enterocyte efflux sterol transporters such as ABCG5 and ABCG8.

The objective of this study was to examine the effects of plant sterols and/or glucomannan on lipid profiles and cholesterol kinetics in hyperlipidemic individuals with or without type 2 diabetes. It was hypothesized that plant sterols and glucomannan reduce circulating cholesterol levels and may have an additive or synergistic effect when combined by reducing cholesterol absorption. Thirteen type 2 diabetics and sixteen non-diabetics all mildly hypercholesterolemic free living subjects participated in a randomized crossover trial consisting of 4 phases, 21 days each. Subjects consumed plant sterols and glucomannan during the trial. Overall reductions in total and LDL-cholesterol levels were greater (P<0.05) after consumption of the combination supplement. Effects of supplements were not different between diabetics and non-diabetics. No significant changes were observed in cholesterol absorption or synthesis in both diabetics and non-diabetics. The intake of plant sterols and glucomannan together may be an alternative approach in reducing blood cholesterol levels.

The objective of this research was to examine the effects of sitosterol and sitostanol supplementation on plasma cholesterol levels and cholesterol metabolism in hypercholesterolemic subjects consuming a fixed foods diet in a four-phase crossover design. It was hypothesized that addition of either phytosterols, phytostenols, or a 50:50 mixture of sterols and stanols to butter would reduce circulating cholesterol levels, despite butter's hypercholesterolemic effect, through actions involving cholesterol absorption, synthesis, and turnover rates. The data obtained indicate that in their free, unesterified form, plant sterols and stanols lower plasma LDL cholesterol equivalently in hypercholesterolemic subjects. Results of this study provide new data that phytosterols and stanols function by suppressing cholesterol absorption while increasing cholesterol synthesis, however, the de-suppression in synthesis cannot fully compensate for the decrease in absorption making the treatment effective, thus may assist in the development of a food which offers health-promoting advantages related to the prevention of cardiovascular disease.

Background. A high ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, in addition to increased levels of small low-density lipoprotein (LDL) particles, are important indicators of cardiovascular disease risk. Therefore, interventions that combine the lowering of total cholesterol and raising of HDL cholesterol concentrations that also increase LDL particle size, may be preventive against cardiovascular disease. Plant sterols decrease total cholesterol and LDL cholesterol levels by 10-15%, while exercise increases HDL cholesterol levels by 4-22%. In view of their complementary effects, combining plant sterols with exercise would appear to be an effective lifestyle therapy to decrease the risk of future cardiovascular disease.
Objective. The aim of this study was to examine the independent and combined effects of plant sterols and exercise on blood lipid levels, and LDL particle size in previously sedentary, hypercholesterolemic adults. An additional objective of this trial was to assess the underlying mechanism by which this combination therapy modulates whole body cholesterol metabolism, to in turn improve lipid profiles.
Methods. In an 8-week, parallel-arm trial, 84 subjects were randomized to 1 of 4 interventions: (1) plant sterols and exercise,(2) plant sterols alone, (3) exercise alone, or (4) control. Blood lipid concentrations were measured using enzymatic kits, and LDL particle size was assessed using polyacrylamide gel electrophoresis. Cholesterol absorption and synthesis were determined using the single isotope single tracer technique and the deuterium incorporation approach, respectively.
Results. Plant sterol supplementation decreased (P < 0.01) total cholesterol concentrations by 8.2% when compared to baseline. Exercise increased (P < 0.01) HDL cholesterol levels by 7.5% while decreasing (P < 0.01) triglyceride concentrations by 13.3% when compared to baseline. Exercise reduced (P < 0.05) post-treatment LDL peak particle size from 255 to 253 A, and decreased (P < 0.05) the proportion of large LDL particles by 13.1%. Plant sterols had no effect on particle size distribution. Plant sterol supplementation decreased (P < 0.01) intestinal cholesterol absorption by 18%, while exercise had no effect on cholesterol absorption. Non-significant increases in cholesterol synthesis rates of 63%, 59%, and 57%, were observed in the combination, exercise, and plant sterol groups, respectively, relative to control.
Conclusion. These findings suggest that this combination therapy yields the most favourable alterations in lipid profiles when compared to each intervention alone. This combined intervention exerts its beneficial effects on lipid profiles by suppressing intestinal cholesterol absorption. Therefore, this lifestyle therapy may be an effective means of decreasing the risk of cardiovascular disease in hypercholesterolemic adults.

The objective of this study was to compare the effect of phytosterols (PS) on lipid profiles and cholesterol kinetics of hypercholesterolemic individuals with or without type 2 diabetes. It was hypothesised that the response to PS would differ between both groups due to different lipid metabolism. During this randomised, double blind, crossover trial, participants consumed a controlled diet with placebo or PS for 21 days.
Plasma total cholesterol (TC) decreased with placebo and PS (10.9% and 9.7% in non-diabetic versus 11.6% and 13.6% in diabetic participants, p < 0.05). Plasma low-density lipoprotein cholesterol (LDL) significantly decreased with PS in both groups. The reduction in LDL with PS was greater in diabetic compared to non-diabetic individuals (29.8% versus 14.9%, p < 0.05). Cholesterol absorption decreased on average (p = 0.06) by 26.5% with PS compared with placebo in the diabetic group only. Therefore, a controlled heart healthy diet reduced TC and LDL concentrations in non-diabetic and diabetic individuals. Adding PS as adjuncts to a hypocholesterolemic dietary treatment was associated with lower LDL concentrations and cholesterol absorption in hypercholesterolemic participants with type 2 diabetes.

The purpose of the present study was to determine the acute effects of strenuous exercise on the following blood constituents: total cholesterol (TC) 1 triglycerides (TG) 1 high density lipoproteins (HDL-C) 1 and low density lipoproteins (LDL-C). A single case study was performed during a 20 day testing period. Two century bicycle rides ( 100 miles) were used as the strenuous exercise bouts. Blood samples were drawn each day and immediately after each 100 mile ride. A pre-set exercise and diet regimen were followed every day of the 20 day procedure. A t-test upon TC 1 TG 1 HDL-C 1 and LDL-C was done to determine the statistical significance between two 100 mile cycling rides and the training days. The change upon TC was an increase of 11.1mg/dl and the change upon TG was an increase of 66.8mg/dl. The t-tests upon both of these variables were found to be significant at the <0.05 level. The change upon HDL-C was an increase of 3.2mg/dl but a ttest showed no statistical significance at the <0.05 level. The change upon LDL-C was a decrease of 2.6mg/dl but a t-test showed no statistical significance at the <0.05 level. Total cholesterol to HDL-C ratio (TC/HDL-C) did not change and a t-test showed no statistical significance at the <0.05 level. The ratio stayed at 2.5 for the duration of the study period. It was determined that an acute bout of exercise significantly changed TC and TG levels. Total cholesterol mean values changed from 106.4mg/dl ± 1.11 to 117.5mg/dl ± 3. 53. Mean TG values changed from 66. 2mg/dl ± 4. 08 to 113mg/dl ± 16.97. The acute bout of exercise did not significantly change HDL-C or LDL-C. possibilities are discussed.

The purpose of this study was to determine the effectiveness of group nutrition and physical activity education classes in lowering cholesterol levels of worksite employees at 6-and 12-month intervals. A total of 32 participants were followed through the study. The group of participants included 24 female and 8 males, all over the age of 40. The data were analyzed using one-way ANOV A with repeated n1easures, post¬hoc analysis, Pearson's correlation coefficient, and ANCOV A to test six null hypotheses. Statistically significant differences in HDL cholesterol levels were found between baseline and 12 months (p=O.OOO) and between 6 months and 12 months (p=O.OOO). Statistically significant differences were also found in TCIHDL cholesterol ratios between baseline and 12 months (p=0.02) and between 6 months and 12 months (p=0.021).
Department of Family and Consumer Sciences

To examine the effect of diet fat type on rates of cholesterol synthesis and esterification during feeding and fasting, nine healthy male subjects were fed solid-food diets of 40% fat as predominantly either olive oil (MONO), safflower-oil margarine (POLY), or butter (SAT). At the end of each two-week diet trial, subjects were given deuterium (D) oxide orally and de novo synthesis was measured from D incorporation into cholesterol and interpreted as rates of fractional synthesis (FSR) (pools/day) into the rapidly exchangeable free cholesterol (FC) pool. Absolute synthesis rates (ASR) were calculated as the product of FSR and the FC pool. Pool size for each subject was obtained from analysis of the specific activity decay curve of an intravenous injection of 4-14C-cholesterol over nine months. Synthesis was measured over two consecutive 12-h fed periods followed by two consecutive 12-h fasted periods. Serum samples were also assayed for lathosterol concentration, an index of cholesterol synthesis. Serum cholesterol and non-HDL cholesterol concentrations were highest on the SAT diet, lowest (P<0.001) on the POLY diet and intermediate on the MONO diet, triglyceride levels were greater (P<0.03) on the SAT diet than on the POLY diet, and HDL levels were lowest (P<0.05) on the SAT diet and highest on the MONO diet. Cholesterol D enrichment and FSR during each 12-h period were greater (P<0.014) on the POLY diet than on the SAT diet; MONO enrichment and FSR were not significantly different from those on the other two diets. Similar results were obtained for rates of cholesterol esterification (P<0.001). Deuterium enrichment data suggested, and lathosterol data confirmed, that free cholesterol synthesis was greater during the fed period than during the fasted period (P<0.01); however, this could not be confirmed for rates of cholesterol esterification. Results suggest that POLY fat feeding augments de novo cholesterol synthesis without adverse effects on total serum cholesterol concentrations, and that the deleterious effects of SAT fat on serum cholesterol are not brought about by augmented de novo synthesis. Finally, the combination of deuterium incorporation and mathematical modelling produces estimates of daily cholesterol synthesis which are compatible with those invoked by more laborious techniques.

Lam, Cheuk Kai.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2007.
Includes bibliographical references (leaves 148-173).
Abstracts in English and Chinese.
ACKNOWLEDGEMENTS --- p.i
ABSTRACT --- p.ii
LIST OF ABBREVIATIONS --- p.vi
TABLE OF CONTENTS --- p.x
Chapter CHAPTER 1 --- GENERAL INTRODUCTION
Chapter 1.1 --- Introduction to Cholesterol and Its Related Diseases --- p.1
Chapter 1.1.1 --- Chemistry of cholesterol --- p.1
Chapter 1.1.2 --- Physiological importance of cholesterol --- p.1
Chapter 1.1.3 --- Pathological effects of cholesterol --- p.3
Chapter 1.1.3.1 --- Mechanism of atherosclerosis --- p.3
Chapter 1.2 --- Cholesterol Homeostasis --- p.6
Chapter 1.2.1 --- Liver as the main organ for cholesterol metabolism --- p.6
Chapter 1.2.2 --- Regulatory sites of cholesterol metabolism --- p.6
Chapter 1.2.2.1 --- Regulation of cholesterol absorption by acyl coenzyme A: cholesterol acyltransferase (ACAT) --- p.6
Chapter 1.2.2.2 --- Sterol regulatory element-binding protein 2 (SREBP-2) as a transcription factor for 3 -hydroxy-3 -methylglutaryl coenzyme A reductase (HMGR) and low-density lipoprotein receptor (LDLR) --- p.10
Chapter 1.2.2.3 --- Roles ofLDLR --- p.11
Chapter 1.2.2.4 --- Rate limiting role of HMGR in cholesterol de novo synthesis --- p.14
Chapter 1.2.2.5 --- Roles of liver-X-receptor-a (LXR-a) in cholesterol catabolism --- p.16
Chapter 1.2.2.6 --- Roles of CYP7A1 in catabolism of cholesterol into bile acids --- p.19
Chapter 1.2.2.7 --- Roles of cholesterol ester transfer protein (CETP) in maintaining cholesterol distribution in blood --- p.22
Chapter CHAPTER 2 --- EFFECT OF OCTADECAENOIC ACIDS ON BLOOD CHOLESTEROL IN HAMSTERS
Chapter 2.1 --- Introduction --- p.25
Chapter 2.1.1 --- Effects of polyunsaturated fatty acids (PUFAs) on blood cholesterol --- p.25
Chapter 2.1.2 --- Differential effects of 18-C PUFAs on lowering blood cholesterol in vivo --- p.25
Chapter 2.1.3 --- "Structures, metabolism and conjugation of octadecaenoic acids (ODA)" --- p.26
Chapter 2.1.4 --- Objectives --- p.26
Chapter 2.2 --- Experiment 1 --- p.28
Chapter 2.2.1 --- Materials and methods --- p.28
Chapter 2.2.1.1 --- Experimental fatty acids --- p.28
Chapter 2.2.1.1.1 --- Isolation of LN from flaxseed --- p.28
Chapter 2.2.1.1.2 --- Isolation of CLN from tung seed --- p.28
Chapter 2.2.1.2 --- Animals --- p.29
Chapter 2.2.1.3 --- Diets --- p.30
Chapter 2.2.1.4 --- Plasma lipid measurements --- p.30
Chapter 2.2.1.5 --- Plasma CETP activity measurement --- p.30
Chapter 2.2.1.6 --- "Measurement of liver SREBP-2, LDLR, HMGR and CYP7A1 protein abundance by Western blotting" --- p.34
Chapter 2.2.1.7 --- "Measurement of hepatic SREBP-2, LDLR, HMGR, LXR, CYP7A1, CETP, SR-B1 and LCAT mRNA by real time PCR" --- p.35
Chapter 2.2.1.7.1 --- Extraction of mRNA --- p.35
Chapter 2.2.1.1.2 --- Complementary DNA synthesis --- p.36
Chapter 2.2.1.7.3 --- Real-time polymerase chain reaction (PCR) anaylsis --- p.36
Chapter 2.2.1.8 --- Determination of cholesterol in liver --- p.37
Chapter 2.2.1.9 --- Determination of fecal neutral and acidic sterols --- p.38
Chapter 2.2.1.9.1 --- Determination of fecal neutral sterols --- p.39
Chapter 2.2.1.9.2 --- Determination of fecal acidic sterols --- p.41
Chapter 2.2.1.10 --- Statistics --- p.43
Chapter 2.2.2 --- Results --- p.44
Chapter 2.2.2.1 --- Growth and food intake --- p.44
Chapter 2.2.2.2 --- Organ weights --- p.44
Chapter 2.2.2.3 --- "Effects of ODA on serum TC, TG and HDL-C" --- p.44
Chapter 2.2.2.4 --- Effect of ODA on liver cholesterol --- p.48
Chapter 2.2.2.5 --- Effect of ODA on fecal neutral sterol output --- p.48
Chapter 2.2.2.6 --- Effect of ODA on fecal acidic sterol output --- p.48
Chapter 2.2.2.7 --- Effect of ODA on cholesterol balance in hamsters --- p.52
Chapter 2.2.2.8 --- Effect of ODA on plasma CETP activity --- p.52
Chapter 2.2.2.9 --- Correlation between blood TC and liver cholesterol --- p.52
Chapter 2.2.2.10 --- Correlation between blood HDL-C and liver cholesterol --- p.52
Chapter 2.2.2.11 --- Correlation between blood nHDL/HDL ratio and liver cholesterol --- p.52
Chapter 2.2.2.12 --- Effect ofODA on liver SREBP-2 immunoreactive mass --- p.58
Chapter 2.2.2.13 --- Effect of ODA on liver LDLR immunoreactive mass --- p.58
Chapter 2.2.2.14 --- Effect of ODA on liver HMGR immunoreactive mass --- p.58
Chapter 2.2.2.15 --- Effect of ODA on liver LXR immunoreactive mass --- p.58
Chapter 2.2.2.16 --- Effect of ODA on liver CYP7A1 immunoreactive mass --- p.63
Chapter 2.2.2.17 --- Effects ofODA on hepatic CETP mRNA --- p.65
Chapter 2.2.2.18 --- Effects of ODA on hepatic LDLR mRNA --- p.65
Chapter 2.2.2.19 --- Effects of ODA on hepatic LXR mRNA --- p.65
Chapter 2.2.2.20 --- Effects of ODA on hepatic CYP7A1 mRNA --- p.65
Chapter 2.3 --- Experiment 2 --- p.70
Chapter 2.3.1 --- Materials and Methods --- p.70
Chapter 2.3.1.1 --- Experimental diets --- p.70
Chapter 2.3.1.2 --- Animals --- p.70
Chapter 2.3.1.3 --- Intestinal acyl coenzyme A: cholesterol acyltransferase (ACAT) activity measurement --- p.70
Chapter 2.3.1.3.1 --- Preparation of intestinal microsome --- p.71
Chapter 2.3.1.3.2 --- ACAT activity assay --- p.71
Chapter 2.3.2 --- Results --- p.73
Chapter 2.3.2.1 --- Growth and food intake --- p.73
Chapter 2.3.2.2 --- Organ weights --- p.73
Chapter 2.3.2.3 --- "Effect of ODA on serum TC, TG and HDL-C" --- p.73
Chapter 2.3.2.4 --- Effect of ODA feeding on fecal neutral sterol content --- p.77
Chapter 2.3.2.5 --- Effect of ODA feeding on fecal acidic sterol content --- p.77
Chapter 2.3.2.6 --- Effect of ODA feeding on intestinal acyl coenzyme A: acyl cholesterol transferase (ACAT) activity --- p.77
Chapter 2.4 --- Discussion --- p.81
Chapter CHAPTER 3 --- EFFECT OF OCTADECAENOIC ACIDS ON CHOLESTEROL-REGULATING GENES IN HepG2
Chapter 3.1 --- Introduction --- p.86
Chapter 3.1.1 --- HepG2 as a model of cholesterol regulation --- p.86
Chapter 3.1.2 --- Effect of polyunsaturated fatty acids (PUFAs) on cholesterol regulating genes in cultured cells --- p.87
Chapter 3.1.3 --- Objectives --- p.89
Chapter 3.2 --- Materials and Methods --- p.90
Chapter 3.2.1 --- Cell culture --- p.90
Chapter 3.2.2 --- "Measurement of SREBP-2, LDLR, HMGR and CYP7A1 protein abundance by Western blotting" --- p.92
Chapter 3.2.3 --- "Measurement of cellular SREBP-2, LDLR, HMGR, LXR, CYP7A1 and CETP mRNA by real time PCR" --- p.93
Chapter 3.2.4 --- Statistics --- p.93
Chapter 3.3 --- Results --- p.95
Chapter 3.3.1 --- Effect of ODA on HepG2 SREBP-2 immunoreactive mass --- p.95
Chapter 3.3.2 --- Effect of ODA on HepG2 HMGR immunoreactive mass --- p.95
Chapter 3.3.3 --- Effect of ODA on HepG2 LDLR immunoreactive mass --- p.95
Chapter 3.3.4 --- Effect of ODA on HepG2 LXR immunoreactive mass --- p.95
Chapter 3.3.5 --- Effect of ODA on HepG2 CYP7A1 immunoreactive mass --- p.96
Chapter 3.3.6 --- Effect of ODA supplementation on HepG2 SREBP-2 mRNA expression --- p.102
Chapter 3.3.7 --- Effect of ODA supplementation on HepG2 SREBP-2 mRNA expression --- p.102
Chapter 3.3.8 --- Effect of ODA supplementation on HepG2 LDLR mRNA expression --- p.102
Chapter 3.3.9 --- Effect of ODA supplementation on HepG2 LXR mRNA expression --- p.106
Chapter 3.3.10 --- Effect of ODA supplementation on HepG2 CYP7A1 mRNA expression --- p.106
Chapter 3.3.11 --- Effect of ODA supplementation on HepG2 CETP mRNA expression --- p.106
Chapter 3.4 --- Discussion --- p.110
Chapter CHAPTER 4 --- EFFECT OF APPLE POLYPHENOLS ON BLOOD CHOLESTEROL IN HAMSTERS
Chapter 4.1 --- Introduction --- p.114
Chapter 4.1.1 --- Apple is a commonly consumed fruit worldwide --- p.114
Chapter 4.1.2 --- Potential health effects of apples --- p.114
Chapter 4.1.3 --- Abundance of polyphenols in apple --- p.115
Chapter 4.1.4 --- Fuji variety of apple --- p.116
Chapter 4.1.5 --- Objectives --- p.116
Chapter 4.2 --- Materials and Methods --- p.118
Chapter 4.2.1 --- Isolation of AP --- p.118
Chapter 4.2.2 --- Characterization of AP extract --- p.118
Chapter 4.2.3 --- Effect of AP on CETP activity in vitro --- p.118
Chapter 4.2.4 --- Effect of AP on blood cholesterol in hamsters --- p.119
Chapter 4.2.4.1 --- Animals --- p.119
Chapter 4.2.4.2 --- Diets --- p.120
Chapter 4.2.4.3 --- Plasma lipids measurement --- p.121
Chapter 4.2.4.4 --- Plasma CETP activity measurement and immunoreactive mass by Western blotting --- p.123
Chapter 4.2.4.5 --- "Measurement of liver SREBP-2, LDL-R, HMG-R and CYP7A1 protein abundance by Western blotting" --- p.124
Chapter 4.2.4.6 --- Statistics --- p.124
Chapter 4.3 --- Results --- p.125
Chapter 4.3.1 --- Polyphenol content in AP --- p.125
Chapter 4.3.2 --- Effect of AP on CETP activity in vitro --- p.125
Chapter 4.3.3 --- Growth and food intake --- p.128
Chapter 4.3.4 --- Organ weights --- p.128
Chapter 4.3.5 --- Effect of AP supplementation on the plasma lipid profile of hamsters --- p.131
Chapter 4.3.6 --- Effect of AP feeding on plasma CETP activity of the hamsters --- p.131
Chapter 4.3.7 --- Effect of AP on plasma CETP immunoreactive mass --- p.134
Chapter 4.3.8 --- Effect of AP on liver SREBP-2 immunoreactive mass --- p.134
Chapter 4.3.9 --- Effect of AP on liver LDLR immunoreactive mass --- p.134
Chapter 4.3.10 --- Effect of AP on liver HMGR immunoreactive mass --- p.134
Chapter 4.3.11 --- Effect of AP on liver CYP7A1 immunoreactive mass --- p.134
Chapter 4.3.12 --- Effect of AP on liver cholesterol level --- p.140
Chapter 4.4 --- Discussion --- p.142
Chapter CHAPTER 5 --- CONCLUSION --- p.145
REFERENCES --- p.148

Lipid metabolism has gained cardiological interest only after statins were demonstrated to reduce cardiovascular disease in secondary and primary prevention. Therefore, this chapter first introduces the physiological and atherogenic properties of lipoproteins, before focusing on interventions. Both the efficacy and safety of statins have been proven in numerous randomized clinical trials. Because there is a considerable residual risk in statin-treated patients, additional approaches have been investigated. The focus is now on further reductions in low-density lipoprotein (LDL) cholesterol levels. First, high-intensity statin regimens were shown to reduce residual risk. Subsequently, ezetimibe was demonstrated, for the first time, to have a beneficial effect as a non-statin lipid intervention. More recently, inhibitors of the enzyme PCSK9 have demonstrated a very high efficacy in reducing LDL cholesterol levels. Although the causality of LDL for atherosclerotic cardiovascular disease has been proven in epidemiological studies, including Mendelian randomization studies, as well as interventional trials, adherence to statins and other therapies is far from optimal. In contrast, interventions to increase high-density lipoprotein (HDL) cholesterol levels could not proven to have further benefits when combined with statins.

Lipid metabolism has gained cardiological interest only after statins were demonstrated to reduce cardiovascular disease in secondary and primary prevention. Therefore, this chapter first introduces the physiological and atherogenic properties of lipoproteins, before focusing on interventions. Both the efficacy and safety of statins have been proven in numerous randomized clinical trials. Because there is a considerable residual risk in statin-treated patients, additional approaches have been investigated. The focus is now on further reductions in low-density lipoprotein (LDL) cholesterol levels. First, high-intensity statin regimens were shown to reduce residual risk. Subsequently, ezetimibe was demonstrated, for the first time, to have a beneficial effect as a non-statin lipid intervention. More recently, inhibitors of the enzyme PCSK9 have demonstrated a very high efficacy in reducing LDL cholesterol levels. Although the causality of LDL for atherosclerotic cardiovascular disease has been proven in epidemiological studies, including Mendelian randomization studies, as well as interventional trials, adherence to statins and other therapies is far from optimal. In contrast, interventions to increase high-density lipoprotein (HDL) cholesterol levels could not proven to have further benefits when combined with statins.

High blood cholesterol and high blood triglycerides are causal risk factors for atherosclerotic cardiovascular disease, which remains the leading cause of death in the developed world. Lipid and lipoprotein metabolism—cholesterol, triglycerides, and fat-soluble vitamins are transported with specific proteins in the blood as multimeric complexes called lipoproteins. Lipid and lipoprotein metabolism are effected by three principal physiological processes: (1) intestinal absorption of dietary lipid and transport in the blood of dietary lipid and lipids, principally derived from the liver (as triglyceride-rich lipoproteins) to peripheral tissues for catabolism by skeletal and cardiac muscle or storage in adipose tissue; (2) return of triglyceride-rich lipoprotein remnants to the liver, hepatic synthesis of low-density lipoprotein, and the transport of cholesterol between peripheral tissues and the liver; and (3) reverse cholesterol transport by high-density lipoprotein (HDL) between peripheral tissues and the liver. Dyslipidaemias are disorders of lipoprotein metabolism in which there is elevation of total cholesterol and/or triglycerides, often accompanied by reduced levels of HDL cholesterol. Causes of dyslipidaemia—particular lipid disorders including polygenic hypercholesterolaemia, familial hypercholesterolaemia, combined hypercholesterolaemia and hypertriglyceridaemia, familial combined hyperlipidaemia, familial dysbetalipoproteinaemia (also called type 3 hyperlipoproteinaemia), and severe hypertriglyceridaemia, as well as secondary or aggravating factors. Management of dyslipidaemia—the key questions are: (1) what classes of lipoproteins and lipids are increased or decreased in the patient’s plasma? (2) Does the patient has a primary (genetic) or secondary (acquired) dyslipidaemia (often contributions from both influences)? (3) Is the patient at risk of atherosclerotic cardiovascular disease or acute pancreatitis? (4) What other risk factors (e.g. hypertension or diabetes) are present? (5) What treatments might be used to address these abnormalities?

Physiologically, in the presence of an intracellular deficit of cholesterol, the LDLR synthesis, expression and function increase, thus uptaking and providing cholesterol to the cell. This process is counter-regulated by PCSK9 expression, the protease inducing LDLR proteolysis, thereby limiting its function maintaining a constant cholesterol intracellular concentration. Accordingly, the balance between PCSK9 and LDLR regulates the intracellular concentration of cholesterol and in consequence has impact on circulating LDL-cholesterol. This chapter reviews the brief and amazing recent history with PCSK9 inhibition from basic science to current clinical recommendations for MAbs-PCSK9. In 2003 and 2005, respectively, the pcsk9 gene mutations, determinants of the “gain of function” of PCSK9 and severe hypercholesterolemia, and the pcsk9 gene mutations with “loss of function” of PCSK9, determinants of hypocholesterolemia were described; subsequently, in 2006, the association between the pcsk9 gene mutations and the “loss of function” of PCSK9 with hypocholesterolemia and reduction of up to 88% for the risk of a coronary event in the “mutant” population versus the control population was published. Since evolocumab clinical research program has completed and published their phases I, II and III results including its cardiovascular outcomes trial, this chapter is focused in reviewing the results of evolocumab clinical research program. In 2009, the effect of a “full human” monoclonal antibody vs PCSK9 in mice and non-human primates was first reported; MAb-PCSK9, AMG-145 (evolocumab) produced in cynomolgus monkeys a doubling in the number of LDLR and an average 75% reduction in circulating LDL-cholesterol. In 2012, the first phase I study with evolocumab versus placebo were reported; this program informed very significant reductions in LDLcholesterol in healthy subjects and patients with familial and non-familial hyper cholesterolemia treated without/with statins; tolerability and safety of evolocumab were similar to placebo. With this evidence, the phase II and III investigations with evolocumab initiated; four years later, the OSLER trial allowed us to envisage the following scenario: MAb-PCSK9 evolocumab have a favorable effect on LDLcholesterol, other apo-B100 lipoproteins and overall mortality and myocardial infarction; all the aforementioned with a very favorable safety and tolerability profile. In the same direction, in 2016 was published the GLAGOV trial, wich demonstrates for the first time that the addition of a non-statin therapy -evolocumab- to the optimal treatment with statins is associated with atheroregression; and finally, in 2017, the FOURIER and the EBBINGHAUS trials were presented, wich confirmed that the addition of evolocumab to the optimal treatment with statins is associated with an additional and significant 20% relative risk reduction -26 months of follow-up- for cardiovascular mortality, myocardial infarction and/or ischemic stroke, all without neurocognitive risk. Beyond the currently approved indications by regulatory agencies, considering the high cost of PCSK9 inhibitors and financial restraints within healthcare budgets, for now and before definitive and necessary cost-effectiveness analysis and price optimization are in place, evolocumab is recommended in specific clinical scenarios reviewed in this chapter.

Elastin is a protein in the extracellular matrix that provides critical mechanical properties of elasticity and extensibility to many connective tissues, including arteries. Such properties of elastin allow arteries to accommodate deformations encountered during physiological functions. Elastin is subjected to changes in mechanical properties upon exposure to various chemical environments. Elastin is a hydrophobic protein, which makes it an attractive site for the deposition of hydrophobic ligands such as cholesterol [1]. Cholesterol is a type of lipid that gradually builds up along arterial wall with aging and pathological conditions.

ABSTRACT Background: Kebo rubber leaves (ficus elastica roxb) contain flavonoids, polyphenols, and tannins. Flavonoids in the leaves of ficus elastica roxb such as catechins, isoflavones are polyphenolic antioxidants from plant metabolites. The leaves of ficus elastica roxb are trusted and proven empirically in the community to reduce cholesterol levels in the blood. Mice choose animals because they are considered to have physiological similarities with humans. This study aimed to determine the effect of ethanol extract of ficus elastica roxb leaves on reducing total cholesterol level in male Swiss Webster mice. Subjects and Method: This was a quasi-experimental study conducted at Biology Laboratory of the Faculty of Agriculture, Fisheries and Biology, University of Bangka Belitung from April to June, 2017. A sample of 25 male Swiss Webster mice was selected at random and allocated into groups. The dependent variable was total cholesterol. The independent variable was the extract of ficus elastica rox. The data were tested by One-Way ANOVA. Result: There were statistically significant mean differences among the study groups (p= 0.002), indicating the effect of ethanol extract of Ficus Elastica Roxb leaves on reducing total cholesterol level in male Swiss Webster mice at various doses. Conclusion: There are statistically significant mean differences among the study groups, indicating the effect of ethanol extract of Ficus Elastica Roxb leaves on reducing total cholesterol level in male Swiss Webster mice at various doses. Keyword: Ethanol extract of Ficus Elastica Roxb leaves, total cholesterol, mice Correspondence: Muhamad Seto Sudirman. School of Health Polytechnic, Pangkalpinang. Email: MuhamadSeto@gmail.com DOI: https://doi.org/10.26911/the7thicph.05.10

The increase in the clinical manifestations of coronary artery disease (CAD) since the 1920s cannot be explained solely in terms of atheroma. Another major process such as thrombogenesis must also be involved. Pathological studies show that thrombosis contributes not only to myocardial infarction but to nearly all cases of sudden coronary death as well. Epidemiologically, it is the coagulation system rather than platelet function that has so far been more rewarding in attempting to identify characteristics of the haemostatic system that are associated with the subsequent risk of CAD. In particular, two clotting factors - factor VII coagulant activity, VIIc, and fibrinogen - may be involved. Factor VII has several characteristics that are required for a system to secure rapid haemostasis after injury. The question is whether an exaggeration of the physiological state of readiness implied by these features may predispose to thrombosis. There are at least four pathways through which high fibrinogen levels, however they are determined, may operate to increase the risk of CAD - involvement in atherogenesis, determination of blood and plasma viscosity, effects on platelet aggregability and an influence on the amount of fibrin formed. The prospective Northwick Park Heart Study (NPHS) has shown an association between high VIIc levels and an increased risk of CAD. NPHS and three other prospective studies have also demonstrated a clear association between high levels of plasma fibrinogen and an increased risk of CAD, this association generally being stronger than for more familiar markers of risk such as the blood cholesterol level. There may well be an interaction between fibrinogen and blood pressure, the occurrence of high levels of both increasing CAD or stroke risk to a greater extent than would be expected from the sum of their separate effects. Several pathological and clinical observations support a “hypercoagulable state” not simply as a concept but as a demonstrable abnormality in which characteristics of the circulating blood influence the course of events. These include the effects of anti-thrombotic agents (particularly oral anticoagulants) on re—infarction rates and the likelihood that high VIIc levels lead to increased levels of thrombin production. The general epidemiology of VIIc and fibrinogen is consistent with the view that high levels of each are of pathogenetic significance. Thus, increasing age, obesity, oral contraceptive usage, the occurrence of the menopause and diabetes are all associated with high levels of VIIc and fibrinogen and with an increased risk of CAD. Psychosocial influences may increase the risk of CAD through effects on the plasma fibrinogen level. There is strong evidence that dietary habit, particularly the consumption of fat, is a leading determinant of the VIIc level. A substantial proportion of the relationship between cigarette smoking and CAD is probably mediated through the plasma fibrinogen level. The most radical implication of a “hypercoagulable state” is for the pharmacological prophylaxis of CAD which, it may turn out, is better approached by anti—thrombotic measures than by the use of lipid-lowering agents.