| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Hypolipidemic and antioxidant activity of the novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor KY-455 in rabbits and hamsters Nakamura, S., S. Kamiya, et al. (2004), Arzneimittelforschung 54(2): 102-8. Abstract: The hypolipidemic and antioxidant effects of N-(4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide (CAS 178469-71-1, KY-455), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were examined in hyperlipidemic rabbits and normolipidemic hamsters. KY-455 inhibited rabbit intestinal, hepatic, macrophage and adrenal ACAT with IC50 values of 0.4, 0.9, 2.9 and 4.1 micromol/l, respectively. KY-455 also inhibited rabbit plasma and LDL-peroxidation (IC50: 0.4 and 1.7 micromol/l, respectively). In rabbits fed a high-cholesterol diet, treatment with KY-455 (30 mg/kg/day) for 8 days markedly lowered serum esterified, free, low-density lipoprotein (LDL)-cholesterol, and hepatic esterified cholesterol levels. KY-455 tended to inhibit ex vivo hepatic ACAT activity 5 h after the final administration. KY-455 also inhibited ex vivo peroxidation of plasma lipids 1 and 5 h after the final administration in rabbits. In normolipidemic hamsters fed a regular diet, treatment with KY-455 (30 mg/kg, twice a day) for 4 days significantly reduced serum esterified, free and LDL-cholesterol, and hepatic esterified and free cholesterol levels. A single administration of KY-455 (30 mg/kg) significantly inhibited ex vivo hepatic ACAT activity in hamsters. In conclusion, KY-455 showed in vitro inhibitory effects on LDL-peroxidation and macrophage ACAT activity at similar concentrations, and in vivo hypolipidemic and ex vivo antioxidative effects at the same dose. Long-term administration of KY-455 is expected to prevent the progress of atherosclerosis by lowering plasma lipid levels, inhibiting both LDL-oxidation and accumulation of cholesterol in macrophages. |
| Hypolipidemic effect of glycosaminoglycans from the sea cucumber Metriatyla scabra in rats fed a cholesterol-supplemented diet Liu, H. H., W. C. Ko, et al. (2002), J Agric Food Chem 50(12): 3602-6. Abstract: The purpose of this study was to determine the hypolipidemic effects of the glycosaminoglycans (GAGs) extracted from a sea cucumber, Metriatyla scabra. Using DEAE column chromatography, two major peaks containing GAGs were obtained: peak 1 (P-1) contained mainly GAGs (as hexuronic acid and hexosamine), whereas P-2 contained mostly free glycan (as fucose) with little hexuronic acid or hexosamine. Therefore, we used only the P-1 fraction (with molecular weights in the range 200-500 kDa) for evaluation of hypolipidemic effects. The lyophilized GAGs were administered orally to male Wistar rats at 5, 10, 20, and 50 mg/kg body weight for six consecutive weeks, during which the rats were fed ad libitum a basal laboratory diet with or without 1% cholesterol. The results show that the 1% cholesterol diet significantly increased plasma total cholesterol, LDL-cholesterol, and atherogenic index. Cholesterol supplementation also significantly increased hepatic TG, cholesterol, phospholipid, and liver weight. When rats fed the 1% cholesterol diet were supplemented orally with the sea cucumber GAGs, plasma levels of total cholesterol, LDL-cholesterol, and atherogenic index were significantly decreased, while HDL-cholesterol was significantly increased, although these effects of the GAGs were only dose-dependent at doses lower than 20 mg/kg b.w. Similarly, the GAGs significantly prevented the increase (p < 0.05) in hepatic contents of triglyceride, cholesterol, and phospholipid. Thus, the present study demonstrates that the sea cucumber GAGs have the potential of being used for reducing the risk of atherosclerosis and hyperlipoproteinemia. |
| Hypolipidemic mechanisms of pectin and psyllium in guinea pigs fed high fat-sucrose diets: alterations on hepatic cholesterol metabolism Vergara-Jimenez, M., K. Conde, et al. (1998), J Lipid Res 39(7): 1455-65. Abstract: Studies were conducted to determine whether pectin (PE) or psyllium (PSY) could reverse the high plasma cholesterol and triacylglycerol (TAG) concentrations induced by high fat (HF) or high sucrose (HS) diets and which are the mechanisms involved. Male guinea pigs were fed either a low fat (LF) or a HF diet with 80% of the carbohydrate energy derived from sucrose. Cellulose was used as control. Plasma LDL cholesterol, TAG, apolipoprotein B, and hepatic cholesteryl ester were lower in guinea pigs fed PE and PSY compared to the control group (P < 0.03). In addition, a 45% higher number of hepatic apoB/E receptors was observed by PE and PSY intake. Hepatic ACAT, HMG-CoA reductase, and cholesterol 7alpha-hydroxylase (C7H) activities were higher in the HF compared to the LF groups (P < 0.01). PSY intake with HF resulted in up-regulation of C7H and HMG-CoA reductase activities (P < 0.05). Additional studies measuring the effects of PE and PSY on low density lipoprotein (LDL) transport and very low density lipoprotein (VLDL) secretion were conducted in the HF groups. ApoB secretion was reduced by pectin and psyllium (P < 0.01) intake while LDL fractional catabolic rates were 100% faster in guinea pigs fed PE or PSY. In these studies the extent of the hypolipidemic response was specific to each fiber type and associated with the amount of sucrose. In addition, PSY altered the activity of hepatic enzymes of cholesterol homeostasis in the HF group. These additional effects of PSY might explain the more dramatic changes in plasma lipid levels associated with PSY consumption. |
| Hypolipidemic therapy and cholesterol absorption Manhas, A. and J. A. Farmer (2004), Curr Atheroscler Rep 6(2): 89-93. Abstract: The advent of safe and effective hypolipidemic therapy has revolutionized the ability of the clinician to optimize abnormalities in the lipid profile. The advent of statin therapy has provided a potent option to decrease low-density lipoprotein and frequently allows achievement of National Cholesterol Education Program target lipid levels with monotherapy. However, lipid goals are frequently not achieved due to inadequate response to therapy or side effects. The role of combination therapy in the optimization of the lipid profile provides a means by which the implementation of pharmacologic agents with synergistic mechanisms of action allows further improvement in circulating levels of low-density lipoprotein cholesterol. Statins have been combined with bile acid resins, fibric acid derivatives, and nicotinic acid. However, bile acid resins, although not systemically absorbed, have significant problems with patient compliance and drug interactions. The implementation of therapy with fibric acid derivatives or nicotinic acid increases the risk of significant side effects such as rhabdomyolysis or liver toxicity. Ezetimibe is a prototype of a new class of agents that specifically block the absorption of cholesterol from the gastrointestinal tract. Ezetimibe has minimal systemic absorption and a metabolic pathway involving enterohepatic circulation that allows for once a day administration due to a prolonged half-life. Ezetimibe lacks the drug interactions that are common with the bile acid resins and it may be utilized as either monotherapy or in combination with other pharmacologic agents. Ezetimibe has a relatively flat dose-response curve and titration is not required. This review centers on the role of pharmacologic agents that act predominantly by the reduction of cholesterol absorption, including colesevelam and ezetimibe. |
| Hypomagnesemia is linked to low serum HDL-cholesterol irrespective of serum glucose values Guerrero-Romero, F. and M. Rodriguez-Moran (2000), J Diabetes Complications 14(5): 272-6. Abstract: Hypomagnesemia is common in diabetic subjects, and is especially common in poorly controlled diabetes, suggesting that diabetes low serum magnesium status is osmotic diuresis-dependent. To assess the relationship between serum magnesium and HDL-cholesterol concentration adjusted by serum glucose values. We assessed the serum magnesium levels of 50 controlled (HbA(1c)7.5% and FPG>/=126 mg/dl) type II diabetic patients, 40 subjects with impaired fasting glucose (IFG) (FPG>/=110 mg/dl and <126 mg/dl) and 190 healthy volunteers (FPG<110 mg/dl). Healthy volunteers were required to have normal blood pressure and normal laboratory tests. Subjects in the groups included were matched by age and body mass index (BMI). The average of diabetes duration was of 11.4+/-6.6, and 10.9+/-6.2 years, P=NS, for the controlled and non-controlled diabetic patients, respectively. Thirty (60.0%) controlled diabetic subjects, 58 (52. 7%) non-controlled diabetic patients, 21 (52.5%) subjects with IFG, and 39 (20.5%) healthy volunteers had serum magnesium levels |
| Hypotensive effect of an inhibitor of cholesterol synthesis (fluvastatin). A pilot study Abetel, G., P. N. Poget, et al. (1998), Schweiz Med Wochenschr 128(7): 272-7. Abstract: To investigate whether fluvastatin lowers cholesterol and blood pressure in hypertensives and hypercholesterolemic patients, 23 patients followed by their medical practitioner received 40 mg fluvastatin once a day for 12 weeks. Arterial blood pressure was measured by continuous ambulatory monitoring. Total mean cholesterol (mmol/l) was lowered from 7.98 +/- 1.21 to 6.25 +/- 0.88 and the atherogenic index from 7.26 +/- 2.11 to 5.49 +/- 1.35. Mean arterial systolic and diastolic blood pressure (mm Hg) was reduced from 144.8 +/- 13.7 to 138.6 +/- 18 and from 97.3 +/- 9.1 to 92 +/- 10.8. In responders (n = 12), blood pressure decreased from 142.6 +/- 11 to 126.4 +/- 11.1 and from 99.6 +/- 7.1 to 88.3 +/- 6.5. In conclusion, fluvastatin prescribed in a dose of 40 mg/day for 3 months to 23 hypertensives and hypercholesterolemic patients lowers the cholesterol level and lowers blood pressure. Lowering of blood pressure is independent of lowering of cholesterol. |
| Hypothesis: low serum cholesterol, suicide, and interleukin-2 Penttinen, J. (1995), Am J Epidemiol 141(8): 716-8. Abstract: An excess mortality for violence (suicides and injuries) has been observed following the use of cholesterol-lowering drugs. It has been suggested that low cholesterol is associated with depression by modifying the serotonin metabolism. In this paper, a new hypothesis concerning the association among serum lipids, depression, and atherosclerosis is proposed. The hypothesis is based on epidemiologic evidence concerning serum lipids, depression, violent deaths, and atherosclerosis. It is also based on previous results concerning a cytokine, interleukin-2. Recent observations indicate that interleukin-2 has an important role in lipid metabolism, depression, and atherosclerosis. |
| Hypoxic effects on cholesterol metabolism of cultured rat aortic and brain microvascular endothelial cells, and aortic vascular smooth muscle cells Arai, Y., M. Sasaki, et al. (1996), Tohoku J Exp Med 180(1): 17-25. Abstract: We investigated hypoxic effects on cholesterol metabolism in cultured brain microvascular endothelial cells (BEC), aortic endothelial cells (AEC) and aortic vascular smooth muscle cells (VSMC) from rat. In control conditions, acid lipase activities in BEC and AEC were higher than that in VSMC. Acyl-Coenzyme A: cholesterol acyltransferase (ACAT) activities in control cells of BEC and AEC were lower than that of VSMC. Hypoxic treatment caused decreased acid lipase activity. ACAT activity decreased in VSMC. High pressure lipid chromatography (HPLC) study showed that hypoxia caused decreased contents of cholesterol and cholesteryl esters especially in AEC. We suggested that there is different cholesterol metabolism in the hypoxic treatment among endothelial cells and smooth muscle cells. |
| I am 70 and have a cholesterol level of 250 mg/dl. Am I right to be concerned? Robb-Nicholson, C. (1998), Harv Womens Health Watch 5(7): 7. |
| I am a 60 year-old woman and have a question about my cholesterol levels. My total cholesterol level is normal (just over 200) but my HDL is low, only 28. Should I be taking a cholesterol-lowering medicine? Lee, T. H. (1999), Harv Heart Lett 9(7): 8. |
| I705 variant in the low denisty lipoprotein receptor gene has no effect on plasma cholesterol levels Heath, K. E., R. A. Whittal, et al. (2000), J Med Genet 37(9): 713-5. |
| Iatrogenic profound hypoalphalipoproteinaemia: an unrecognised cause of very low HDL cholesterol Murphy, M. J., A. Duncan, et al. (1995), Postgrad Med J 71(838): 498-500. Abstract: A significant reduction in plasma high density lipoprotein (HDL) cholesterol is a recognised consequence of treatment with probucol. By contrast, fibrate therapy in general has the opposite effect. We report two cases where the combination of probucol and a fibrate led to profoundly reduced plasma levels of HDL cholesterol associated with very low levels of apolipoprotein A-I (apoA-I). In the first, bezafibrate was added to probucol, and in the second, probucol added to a combination of simvastatin and fenofibrate. In both cases, plasma levels of HDL and apoA-I returned towards normal after discontinuation of one or both drugs, indicating that the reduction was reversible. |
| Identification and cholesterol quantification of low density lipoprotein subclasses in young adults by VAP-II methodology Kulkarni, K. R., D. W. Garber, et al. (1995), J Lipid Res 36(11): 2291-302. Abstract: Low density lipoprotein (LDL) particles are heterogeneous in size, density, and chemical composition; small, dense LDL may be more atherogenic than large, buoyant LDL. We have developed a rapid microscale method called LDL VAP-II (Vertical Auto Profile-II) for quantification of cholesterol in LDL subclasses. The method is based upon a short (1 h) single vertical spin density-gradient ultracentrifugation and on-line VAP-II analyzer. LDL VAP-II is rapid and reproducible. Using this method five LDL subclasses, designated as LDL-1 (most buoyant) through LDL-5 (most dense), have been identified in a population consisting of 195 medical students (ages, 22-29 years). The Rf (relative position of the major LDL peak in the density gradient; the higher the Rf value, the lower the peak density) was significantly positively correlated with cholesterol levels of high density lipoprotein (HDL) (r = 0.594), HDL3 (0.350) and HDL2 (0.625), and significantly negatively correlated with triglycerides (TG) (-0.355) and cholesterol levels of very low density lipoprotein (VLDL) (-0.386) and intermediate density lipoprotein (IDL) (-0.432). These results are consistent with those obtained by other investigators. The Rf value was significantly correlated with peak particle diameter as determined by non-denaturing gradient gel electrophoresis (r = 0.859). In a forward stepwise multivariate analysis comparing Rf with sex, VLDL, LDL, Lpa, IDL, HDL3, HDL2, and triglyceride, only HDL2 remained in the model. |
| Identification and management of vascular risk: beyond low density lipoprotein cholesterol Ross, J. L., M. A. Manuszak, et al. (2003), Aaohn J 51(12): 521-31; quiz 532-3. Abstract: Vascular disease is basically an inherited metabolic disease. Eighty percent of individuals who develop disease have the same blood cholesterol levels as individuals who do not develop disease. With vascular disease pervasive throughout the world and current assessment techniques insufficient to identify those at risk, use of a multifactorial approach to vascular assessment is prudent. Assays are currently available that enable health care providers to determine risk beyond those traditionally used. These "novel" risk factors appear to be additive (Brown, 2001; Rader, 2000a, 2002; Superko, 1995), and when combined with traditional factors, LDL can be adjusted to prevent disease. In individuals with established disease, these factors can be instrumental in identifying an appropriate treatment protocol for halting the progression of disease. To date, the health care establishment as a whole has done a poor job of identifying and thoroughly treating cardiovascular risk. Even when risks were identified, often treatment protocols have not been aggressive enough to reach targeted goals (Hoerger, 1998; Jacobson, 2000; NHANES III, 2000). The unique role of the occupational health nurse offers an opportunity to follow a client during long periods of time. This is useful in establishing trust and getting to know the specific problems of each individual. The occupational health nurse, therefore, stands at the threshold of change for the client, easing and assisting the client to reach individual goals. This group of nurses can play a significant role in forging prevention and stamping out the number one killer of the American population. |
| Identification and molecular analysis of two apoB gene mutations causing low plasma cholesterol levels Welty, F. K., J. Ordovas, et al. (1995), Circulation 92(8): 2036-40. Abstract: BACKGROUND: Familial hypobetalipoproteinemia (FHB) is an autosomal codominant disorder characterized by abnormally low plasma levels of apoB and LDL cholesterol. Heterozygotes for FHB almost always have plasma LDL cholesterol levels < 70 mg/dL and are asymptomatic. Because the low cholesterol levels may protect FHB heterozygotes from coronary heart disease, the mechanisms for FHB are of considerable interest. METHODS AND RESULTS: The plasma lipoproteins of 29 subjects with LDL cholesterol levels < 70 mg/dL were examined by SDS-PAGE. One subject who had virtually undetectable levels of LDL cholesterol had a truncated apoB, apoB-44.4, in his lipoproteins; a second subject with an LDL cholesterol level of 44 mg/dL had apoB-55 in his lipoproteins. The apoB-44.4 (2014 amino acids in length) resulted from a frameshift caused by an 11-bp insertion in exon 26 of the apoB gene; the apoB-55 (2494 amino acids) was caused by a nonsense mutation in exon 26 of the apoB gene. The apoB-55 mutation occurred at a CpG dinucleotide pair, a mutational hot spot, and was identical to a mutation described previously in a subject with hypobetalipoproteinemia. Our subject with apoB-55, however, had a different haplotype than the subject described previously, suggesting that the two apoB-55 mutations may have arisen independently. Of note, the apoB-55 proband's father, who had very low cholesterol levels and who probably carried the apoB-55 mutation, had significant coronary and aortic atherosclerosis at autopsy. CONCLUSIONS: In a study of adults with low LDL cholesterol levels, we discovered two subjects with truncated apoB proteins and identified the responsible mutations. ApoB gene mutations causing truncated apoB are not particularly rare in subjects with low cholesterol levels. The role of these mutations in preventing atherosclerosis deserves further study. |
| Identification and quantification of cholesterol and cholesterol oxidation products in different types of Iberian hams Petron, M. J., J. A. Garcia-Regueiro, et al. (2003), J Agric Food Chem 51(19): 5786-91. Abstract: Cholesterol and cholesterol oxidation products (COPs) were determined in four different groups of dry-cured Iberian hams, based on the feeding received by pigs and their degree of crossbreeding. After lipid extraction, GC-FID for cholesterol determination and GC-MS to analyze COPs were used. Cholesterol content ranged from 30 to 34 mg/100 g of muscle. Some of the COPs analyzed, such as 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, and 7-ketocholesterol, were detected in all of the samples. The major cholesterol oxide was 7-ketocholesterol; its concentration ranged from 57 to 71 microg/100 g of muscle. The content of cholesterol and cholesterol oxides in intramuscular lipids of hams was not affected by diet or crossbreeding of Iberian pigs. |
| Identification of a cholesterol-regulated 180-kDa microsomal protein in rat hepatocytes Haro, D., P. F. Marrero, et al. (1990), Eur J Biochem 188(1): 123-9. Abstract: The immunoprecipitation by antibodies to 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of extracts of 35Smethionine-pulse-labelled isolated hepatocytes, followed by electrophoresis and fluorography, showed the presence not only of 97-kDa HMG-CoA reductase, but also of another protein of 180 kDa. Boiling the immunoprecipitates both in the presence and in the absence of 2-mercaptoethanol, followed by SDS/polyacrylamide gel electrophoresis both in the presence and in the absence of 8 M urea, was not found to change the ratio of 180-kDa/97-kDa proteins. These facts suggest that the 180-kDa protein is not an aggregated form of HMG-CoA reductase. A different batch of antibodies obtained from a newly purified HMG-CoA reductase fully titrated the reductase activity, but did not immunoprecipitate the 180-kDa protein, showing that there is no cross-reactivity between these proteins. The 180-kDa polypeptide is a glycoprotein of N-linked high-mannose oligosaccharide chains, which is not processed on the Golgi system. The apparent molecular mass of the carbohydrate is 16 kDa. The incubation of rat hepatocytes with sterols produces, on the one hand, a decrease in the rate of synthesis, and on the other hand, an acceleration in the turnover rate of the 180-kDa protein. In addition, mevalonate is known to decrease its rate of synthesis. The carbohydrate-free 164-kDa protein was found to degrade only a tenth as fast as the glycoprotein and, furthermore, the degradation was no longer accelerated by sterols. These results support the notion that the 180-kDa protein is not a modified form of 97-kDa reductase, but probably a different protein related to cholesterol metabolism, and also that the N-linked, high-mannose chains, which are bound to the glycoprotein, are required for rapid and controlled degradation of the protein. |
| Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption Lee, M. H., K. Lu, et al. (2001), Nat Genet 27(1): 79-83. Abstract: The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients. |
| Identification of a novel cis-acting element participating in maximal induction of the human low density lipoprotein receptor gene transcription in response to low cellular cholesterol levels Mehta, K. D., R. Chang, et al. (1996), J Biol Chem 271(52): 33616-22. Abstract: In this paper, we present both in vivo and in vitro evidence for the presence of a novel cis-acting regulatory element that is required for maximal induction of the human low density lipoprotein (LDL) receptor gene following depletion of cellular sterols in HepG2 cells. First, in vivo dimethyl sulfate footprinting of the human LDL receptor promoter before and after transcriptional induction in HepG2 cells revealed protection from -145 to -126, 5'-GAGCTTCACGGGTTAAAAAG-3' (referred to as FP1 site). Second, transient transfections of HepG2 cells with promoter luciferase reporter constructs containing the FP1 site resulted in significant enhancement (approximately 375%) of reporter gene expression in response to low levels of sterols compared with parallel plasmid without the FP1 site. In addition, this response was markedly attenuated on nucleotide substitutions within the FP1 site. Third, by electrophoretic mobility shift assays, the FP1 sequence was found to bind protein(s) from HepG2 nuclear extracts in a sequence-specific manner. In vitro binding of the FP1 mutants paralleled the results obtained for their in vivo transcription. On the basis of competition profiles, the FP1-binding factor is different from the known transcription factors binding to the AT-rich CArG and GArC motifs. Furthermore, the FP1-binding protein is not specific to HepG2 cells because nuclear factor(s) with the same specificity was observed in nuclear extracts of non-hepatic HeLa cells. We conclude that transcriptional induction of the LDL receptor gene in response to sterol depletion is mediated, in part, by an highly conserved novel cis-acting element through the binding of specific nuclear protein(s). |
| Identification of a receptor mediating absorption of dietary cholesterol in the intestine Hauser, H., J. H. Dyer, et al. (1998), Biochemistry 37(51): 17843-50. Abstract: Here we show that scavenger receptor class B type I is present in the small-intestine brush border membrane where it facilitates the uptake of dietary cholesterol from either bile salt micelles or phospholipid vesicles. This receptor can also function as a port for several additional classes of lipids, including cholesteryl esters, triacylglycerols, and phospholipids. It is the first receptor demonstrated to be involved in the absorption of dietary lipids in the intestine. In liver and steroidogenic tissues, the physiological ligand of this receptor is high-density lipoprotein. We show that binding of high-density lipoprotein and apolipoprotein A-I to the brush border membrane-resident receptor inhibits uptake of cholesterol (sterol) into the brush border membrane from lipid donor particles. This finding lends further support to the conclusion that scavenger receptor BI catalyzes intestinal cholesterol uptake. Our findings suggest new therapeutic approaches for limiting the absorption of dietary cholesterol and reducing hypercholesterolemia and the risk of atherosclerosis. |