Cholesterol Journal Articles

Record 11181 to 11200

Routine cholesterol surveillance in childhood
Feldman, W. (1990), Pediatrics 86(1): 150-1.

Routine diagnostic testing for apoA-I, apo-B, Lp(a), and LDL cholesterol in clinical laboratories
Schaefer, E. J. and J. R. McNamara (1994), Clin Lab Sci 7(4): 205-8.

RP 64477: a potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase with low systemic bioavailability
Bello, A. A., C. Bright, et al. (1996), Biochem Pharmacol 51(4): 413-21.
Abstract: RP 64477 (N-butyl-3-(p-decyloxybenzamido)-4-(methylthio)benzamide) has been shown to be a potent inhibitor of the cholesterol esterifying enzyme Acyl-coenzyme A:cholesterol O-acyltransferase (EC 2.3.1.26; ACAT) in intestinal, hepatic, adrenal, and arterial tissue preparations obtained from a range of animal species. Drug concentrations producing 50% inhibition of enzyme activity (IC50 values) ranged from 14-283 nM. Inhibition by RP 64477 in a rabbit intestinal enzyme preparation was shown to be non-competitive with respect to the substrate oleoyl-CoA. In whole cell assays using human intestinal (CaCo-2), hepatic HepG2) and monocytic (THP-1) cell lines, RP 64477 inhibited ACAT activity with IC50s of 113, 503, and 180 nM, respectively. RP 64477 (0.03% w/w by diet) reduced significantly cholesterol absorption in cholesterol/cholic acid-fed rats from 94+/- 8% to 65 +/- 4%. In cholesterol-fed rabbits, cholesterol absorption was reduced from 72 +/- 5% to 50 +/-5% and 44 +/- 5% at dose levels of 10 and 30 mg kg-1 b.i.d., respectively. Plasma cholesterol levels were reduced dose-dependently in both cholesterol/cholic-acid-fed rats and cholesterol-fed rabbits. Neither cholesterol absorption nor plasma cholesterol levels were reduced significantly in animals maintained on standard laboratory diets. Pharmacokinetic studies indicated that RP 64477 were very poorly absorbed following oral administration to rats. Plasma levels of drug were < 2 ng mL-1 following a dose of 2000 mg kg-1 p.o. When radiolabelled RP 64477 was administered orally, limited absorption was indicated by the overwhelming elimination of radioactivity in the faces (96.4% of administered material) coupled with low renal clearance (0.6% of dose) and biliary excretion (0.05% of dose). In conclusion, this work shows that RP 64477 is a potent inhibitor of ACAT obtained from a range of animal species and man. Inhibition of cholesterol absorption and hypocholesterolaemic activity has been demonstrated in rats and rabbits maintained on diets supplemented with cholesterol. Pharmacokinetic studies indicate low systemic exposure to RP 64477 as a result of limited absorption of this drug.

RPR 101821, a new potent cholesterol-lowering agent: inhibition of squalene synthase and 7-dehydrocholesterol reductase
Amin, D., R. Z. Rutledge, et al. (1996), Naunyn Schmiedebergs Arch Pharmacol 353(2): 233-40.
Abstract: RPR 101821 (trans-2-4-(benzoxazol-2-yl)-phenylmethoxy amino cyclohexane hydrochloride) is a potent cholesterol-lowering agent in rodents and marmoset. The compound inhibited rat liver microsomal squalene synthase (IC50 = 1 nM) and 7-dehydrocholesterol (7DHC) reductase (IC50 = 1 microM; Lewis et al. 1995). When RPR 101821 (10 mg/kg), the 7DHC reductase inhibitor BM 15.766 (42-4-(4-chlorocinnamyl)piperazine-1-ylethyl benzoic acid; 10 mg/kg) or the HMG-CoA reductase inhibitor lovastatin (30 mg/kg) was given orally to rats at -29 h, -21 h and -5 h, serum cholesterol was reduced by 56%, 46% or 15%, respectively. The reduction in cholesterol with RPR 101821 was associated with an accumulation of 7DHC in serum, suggesting an inhibition of 7DHC reductase. In the presence of BM 15.766, RPR 101821 reduced the serum accumulation of 7DHC in a dose-dependent manner, with complete inhibition at 30 mg/kg, p.o. In Balb-cJ mice, RPR 101821 and lovastatin (50 mg/kg, b.i.d., p.o., for 14 days) lowered serum cholesterol by 67% and 2%, respectively. In marmosets, RPR 101821 and lovastatin (both at a dose of 10 mg/kg, p.o., b.i.d., for 7 days) reduced cholesterol by 28% and 19%, respectively. In summary, RPR 101821 is an orally effective potent cholesterol-lowering agent in rodents and a small primate species. The suggested mechanism of hypocholesterolemic effect is the inhibition of squalene synthase and 7DHC reductase.

RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase
Amin, D., R. Z. Rutledge, et al. (1997), J Pharmacol Exp Ther 281(2): 746-52.
Abstract: Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation of other products of the isoprenoid pathway, such as dolichol and ubiquinone. RPR 107393 3-hydroxy-3-4-(quinolin-6-yl)phenyl-1-azabicyclo2-2-2octane dihydrochloride and its R and S enantiomers are potent inhibitors of rat liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM. One hour after oral administration to rats, RPR 107393 inhibited de novo 14Ccholesterol biosynthesis from 14Cmevalonate in the liver with an ED50 value of 5 mg/kg. Diacid metabolites of 14Cfarnesyl pyrophosphate were identified after acid treatment of the livers of these animals. These results support in vitro data demonstrating that these compounds are inhibitors of squalene synthase. In rats, RPR 107393 (30 mg/kg p.o. b.i.d. for 2 days) reduced total serum cholesterol by < or = 51%. In the same paradigm, the HMG-CoA reductase inhibitor lovastatin failed to lower serum cholesterol in rats. In marmosets, RPR 107393 (20 mg/kg b.i.d.) reduced plasma cholesterol concentration by 50% after 1 week of administration; this was greater than the reduction observed with lovastatin or pravastatin, neither of which produced > 31% reduction in plasma cholesterol when administered for 1 week at a dose of 50 mg/kg b.i.d. The R and S enantiomers of RPR 107393 (20 mg/kg p.o. q.d. for 7 days) reduced plasma low density lipoprotein cholesterol by 50% and 43%, respectively, whereas high density lipoprotein cholesterol was unchanged. In summary, RPR 107393 is a potent inhibitor of squalene synthase. It is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset.

RSH/SLO (Smith-Lemli-Opitz) syndrome: designing a high cholesterol diet for the SLO syndrome
Acosta, P. B. (1994), Am J Med Genet 50(4): 358-63.
Abstract: A high cholesterol diet has been suggested to help prevent the poor reproductive outcomes found in heterozygote carriers of fetuses affected with the Smith-Lemli-Opitz (SLO) syndrome. The theory has also been presented that a high cholesterol medical food may enhance myelination of the central nervous system of the infant and prevent demyelination in the child and adult with SLO. Clinical studies are required to test this hypothesis and to determine the optimal composition of such medical foods. FDA requires proof of efficacy and controls nutrient composition, ingredients, and label claims of medical foods.

RSH/Smith-Lemli-Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis
Porter, F. D. (2000), Mol Genet Metab 71(1-2): 163-74.
Abstract: The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation syndrome caused by an inborn error of cholesterol biosynthesis. The RSH/SLOS phenotypic spectrum is broad; however, typical features include microcephaly, ptosis, a small upturned nose, micrognathia, postaxial polydactaly, second and third toe syndactaly, genital anomalies, growth failure, and mental retardation. RSH/SLOS is due to a deficiency of the 3beta-hydroxysterol Delta(7)-reductase, which catalyzes the reduction of 7-dehydrocholesterol (7-DHC) to cholesterol. This inborn error of cholesterol biosynthesis results in elevated serum and tissue 7-DHC levels. The 3beta-hydroxysterol Delta(7)-reductase gene (DHCR7) maps to chromosome 11q12-13, and to date 66 different mutations of this gene have been identified in RSH/SLOS patients. Identification of the biochemical basis of RSH/SLOS has led to development of therapeutic regimens based on dietary cholesterol supplementation and has increased our understanding of the role cholesterol plays during embryonic development.

Rural/urban differences of diabetes--impaired glucose tolerance, hypertension, obesity, glycosolated haemoglobin, nutritional proteins, fasting cholesterol and apolipoproteins in Fijian Melanesians over 40
Russell-Jones, D. L., P. Hoskins, et al. (1990), Q J Med 74(273): 75-81.
Abstract: Two populations of Fijian Melanesians over 40 years of age were compared. The first population was located in a remote rural area and the other in an urban environment. There was no significant difference between the two populations in age, height and diastolic blood pressure. Highly significant differences were observed in mean weight, body mass index, prevalence of impaired glucose tolerance, prevalence of diabetes, mean glycosolated haemoglobin, mean systolic blood pressure, fasting cholesterol, immunological albumin, immunological transferrin, and A1 and B apolipoproteins. The higher value was associated with urban living. Thus urban living is associated with obesity, impaired glucose tolerance, diabetes, higher systolic blood pressure, higher levels of fasting lipids and increased risk factors for cardiovascular disease.

Rye bread decreases serum total and LDL cholesterol in men with moderately elevated serum cholesterol
Leinonen, K. S., K. S. Poutanen, et al. (2000), J Nutr 130(2): 164-70.
Abstract: The objective of this study was to determine the hypocholesterolemic effects of whole meal rye and white wheat breads in healthy humans with elevated serum cholesterol concentrations, and the changes in plasma glucose and insulin concentrations during rye and wheat bread periods. The subjects were 18 men and 22 women with baseline serum cholesterol concentration of 6.4+/-0.2 mmol/L. The study design was a 2x4-wk crossover trial during which each subject randomly consumed rye and wheat breads (20% of daily energy) as part of their usual diet for 4 wk. The bread periods were separated by a 4-wk washout period. Blood samples (after fasting) were collected on two consecutive days at the beginning and end of the bread periods. Serum total cholesterol decreased by 8% (P = 0.002) in men but was not significantly altered in women during the rye bread period. The wheat bread period did not affect any of the variables studied. Analysis of the serum lipids in tertiles of rye bread consumption confirmed the reduction in total cholesterol (P = 0.048) in men and revealed the reduction in LDL cholesterol (P = 0.032); both were dependent on the amount of rye bread consumed (-2, -14 and -10% in total cholesterol and 0, -12 and -12% in LDL cholesterol). Neither rye nor wheat bread influenced the concentrations of glucose and insulin. In conclusion, rye bread is effective in reducing serum total and LDL cholesterol concentrations in men with elevated serum cholesterol. Good compliance with consuming a relatively large amount of rye bread in the usual diet indicates that rye bread offers a practical dietary means of reducing serum cholesterol in men.

S-8921, an ileal Na+/bile acid cotransporter inhibitor decreases serum cholesterol in hamsters
Hara, S., J. Higaki, et al. (1997), Life Sci 60(24): PL 365-70.
Abstract: The ileal Na+/bile acid cotransporter (IBAT) maintains the reabsorption of bile acids from the intestine in the enterohepatic circulation of bile acids. In the present study, we showed that S-8921 could dose-dependently inhibit the uptake of 3H taurocholate in the COS7 cell line which constitutively expresses hamster IBAT. The IC50 value of S-8921 against 60 microM of 3H taurocholate uptake was 66 +/- 8 microM and kinetic analysis revealed that the inhibition by 100 microM of S-8921 was a mixture of competitive and non-competitive types. In vivo administration of S-8921 by its incorporation into diet (0.001-0.1%) caused dose-dependent decrease of serum cholesterol concentrations accompanied by increased fecal excretion of bile acids in hamsters which were not loaded with cholesterol and bile acid. These data suggest that the inhibition of IBAT could decrease serum cholesterol in the non-cholesterol and -bile acid loaded normal condition.

Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study
Pedersen, T. R., K. Berg, et al. (1996), Arch Intern Med 156(18): 2085-92.
Abstract: BACKGROUND: Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. METHODS: The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). RESULTS: The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. CONCLUSION: The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.

Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study)
Zhao, X. Q., J. S. Morse, et al. (2004), Am J Cardiol 93(3): 307-12.
Abstract: The high-density lipoprotein (HDL)-Atherosclerosis Treatment Study showed that simvastatin plus niacin (mean daily dose 13 mg and 2.4 g, respectively) halt angiographic atherosclerosis progression and reduce major clinical events by 60% in patients with coronary artery disease (CAD) who have low HDL, in comparison with placebos, over 3 years. How safe and well-tolerated is this combination? One hundred sixty patients with CAD, including 25 with diabetes mellitus, with mean low-density lipoprotein cholesterol of 128 mg/dl, HDL cholesterol of < or =35 mg/dl (mean 31), and mean triglycerides of 217 mg/dl were randomized to 4 factorial combinations of antioxidant vitamins or their placebos and simvastatin plus niacin or their placebos. Patients were examined monthly or bimonthly for 38 months; side effects (gastrointestinal upset, nausea, anorexia, vision, skin, and energy problems, or muscle aches) were directly queried and recorded. Aspartate aminotransferase, creatine phosphokinase (CPK), uric acid, homocysteine, and fasting glucose levels were regularly monitored. A safety monitor reviewed all side effects and adjusted drug dosages accordingly. Patients who received simvastatin plus niacin and those on placebo had similar frequencies of clinical or laboratory side effects: any degree of flushing (30% vs 23%, p = NS), symptoms of fatigue, nausea, and/or muscle aches (9% vs 5%, p = NS), aspartate aminotransferase (SGOT) > or =3 times upper limit of normal (3% vs 1%, p = NS), CPK > or =2 times upper limit of normal (3% vs 4%, p = NS), CPK > or =5 times upper limit of normal, new onset of uric acid > or =7.5 mg/dl (18% vs 15%, p = NS), and homocysteine > or =15 micromol/L (9% vs 4%, p = NS). Glycemic control among diabetics declined mildly in the simvastatin-niacin group but returned to pretreatment levels at 8 months and remained stable for rest of the study. This combination regimen was repeatedly described by 91% of treated patients and 86% of placebo subjects as "very easy" or "fairly easy" to take. Thus, the simvastatin plus niacin regimen is effective, safe, and well tolerated in patients with or without diabetes mellitus.

Saiko-ka-Ryukotsu-Borei-To inhibits intimal thickening in carotid artery after balloon endothelial denudation in cholesterol-fed rats
Chung, H. J., I. Maruyama, et al. (2003), Biol Pharm Bull 26(1): 56-60.
Abstract: Oral administration of Saiko-ka-Ryukotsu-Borei-To (SRB), a traditional Chinese formulation, dose dependently inhibited intimal thickening in carotid artery injured by balloon endothelial denudation in cholesterol-fed rats. SRB also inhibited vascular smooth muscle cell (VSMC) proliferation, which is assessed by counting the VSMCs immunoreactive with antiproliferating cell nuclear antigen (PCNA) antibody in the intimal area. VSMC proliferation is considered to play a central role in the development of intimal thickening. SRB slightly, but not significantly, reduced serum total cholesterol and low-density lipoprotein cholesterol. These results indicate that the suppressive effect of SRB on intimal thickening may result from its inhibitory effect against VSMC proliferation, but does not depend on lowering of lipid levels. The balloon injury model used in this study has similar pathological processes to restenosis after percutaneous coronary intervention (PCI). Therefore the present results may provide a new therapeutic strategy using SRB to reduce restenosis after PCI in the treatment of patients with ischemic coronary artery disease. Furthermore, since it is considered that artery restenosis after balloon injury in PCI is "accelerated atherosclerosis, " SRB may have beneficial effects in atherosclerosis that develops over a long clinical course in hyperlipidemia, diabetes, etc.

Salivary cholesterol of healthy adults in relation to serum cholesterol concentration and oral health
Karjalainen, S., L. Sewon, et al. (1997), J Dent Res 76(10): 1637-43.
Abstract: Salivary lipids are mostly glandular in origin, but some are believed to diffuse directly from serum. This diffusion and the role of salivary lipids in oral health have scarcely been studied. Therefore, the serum and saliva cholesterol concentrations and oral health were analyzed in a group of healthy adults (n = 139; 64 men and 75 women; 34.2 +/- 5.2 yrs). Paraffin-stimulated whole saliva was collected, centrifuged (10,000 x g; 30 min, 4 degrees C), and lyophilized, and the cholesterol and other neutral lipids were extracted, separated by thin-layer chromatography, and quantified. The mean +/- SD (range) of saliva cholesterol concentration was 1.20 +/- 0.75 (0.02-5.46) mumol/L, and the saliva cholesterol level of men (1.36 +/- 0.85 mumol/L) was significantly higher than that of women (1.06 +/- 0.64 mumol/L; p < 0.05). Weak positive correlations between saliva and serum cholesterol concentrations and saliva cholesterol and serum non-high-density lipoprotein cholesterol concentrations were found (r = 0.22, p < 0.05; r = 0.28, p < 0.005, respectively). The saliva cholesterol assay detected subjects with high (> or = 6.5 mmol/L) serum cholesterol values, with sensitivity and specificity values of 100% and 29%, respectively. A positive correlation between the body mass index and the level of saliva cholesterol concentration was also found (r = 0.31 p < 0.01). Oral health, microbial counts, or saliva flow rate revealed no differences in subjects with low and high salivary cholesterol level. We conclude that, in healthy adults, saliva cholesterol concentration reflects serum concentration to some extent and can be used to select individuals with high serum cholesterol levels.

S-alk(en)yl cysteines of garlic inhibit cholesterol synthesis by deactivating HMG-CoA reductase in cultured rat hepatocytes
Liu, L. and Y. Y. Yeh (2002), J Nutr 132(6): 1129-34.
Abstract: The effects of water-soluble organosulfur compounds of garlic on hepatic cholesterol biosynthesis in cultured rat hepatocytes were studied. S-Alk(en)yl cysteines, i.e., S-allyl cysteine (SAC), S-ethyl cysteine (SEC) and S-propyl cysteine (SPC) inhibited cholesterol synthesis from (14)Cacetate but not from (14)Cmevalonate. The activity of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase in the cells treated with SAC, SEC and SPC was 30-40% lower than that of the untreated cells. S-Alk(en)yl cysteines did not alter abundance of mRNA coded for HMG-CoA reductase or protein concentration of the enzyme. The ratio of expressed to total activity (E/T) of HMG-CoA reductase was then determined as an index of phosphorylation status of the enzyme. The E/T ratio was reduced 18-29% by SAC, SEC and SPC, resulting primarily from decreased expressed activity. The results suggest that S-alk(en)yl cysteines inhibit cholesterol synthesis by deactivating HMG-CoA reductase via enhanced phosphorylation, but not changing levels of mRNA or the amount of the enzyme. Additionally, of the three S-alk(en)yl cysteines tested, only SAC appears to further decrease the activity of HMG-CoA reductase by increasing sulfhydryl oxidation of the enzyme.

Salmonella enterica serovar Typhimurium requires nonsterol precursors of the cholesterol biosynthetic pathway for intracellular proliferation
Catron, D. M., Y. Lange, et al. (2004), Infect Immun 72(2): 1036-42.
Abstract: We have previously shown that Salmonella enterica serovar Typhimurium infection perturbs the host cholesterol biosynthetic pathway. Here we show that inhibiting the first step of this pathway (3-hydroxy-3-methylglutaryl coenzyme A reductase) reduces the growth of intracellular S. enterica serovar Typhimurium and has no effect on extracellular bacterial growth. Selectively inhibiting synthesis of downstream sterol components has no effect on infection, suggesting that the effect of statins on host nonsterol intermediates is detrimental to bacterial growth. Furthermore, statins also reduce bacterial proliferation in the S. enterica serovar Typhimurium mouse model. This suggests that blocking the production of nonsterol precursors in the host cell can be used to reduce infection.

Salvia miltiorrhiza inhibits intimal hyperplasia and monocyte chemotactic protein-1 expression after balloon injury in cholesterol-fed rabbits
Chen, Y. L., S. P. Yang, et al. (2001), J Cell Biochem 83(3): 484-93.
Abstract: Antioxidants that prevent low density lipoproteins (LDL) from oxidation may inhibit atherosclerosis and post-angioplasty restenosis. Salvia miltiorrhiza (SM) has been shown to inhibit LDL oxidation and reduce atherosclerosis in cholesterol-fed rabbits. The effects of SM on neointimal hyperplasia and monocyte chemotactic protein-1 (MCP-1) expression after balloon injury were studied. Male New Zealand white rabbits were fed a 2% cholesterol diet together with daily SM (4.8 gm/kg body wt.) treatment (SM; n=10) or without SM as a control (C; n=9) for 6 weeks. Probucol-treated (0.6 gm/kg body wt.) rabbits (P; n=9) were used as a positive control group. A balloon injury of the abdominal aorta was performed at the end of the third week. Aortas were harvested at the end of 6 weeks. The plasma cholesterol levels were lowered in SM group. The neointimal hyperplasia in abdominal aortas was significantly inhibited in SM group neointima/media area ratio: 0.63+/-0.05 (SM) versus 0.78+/-0.05 (C); P < 0.05 and in P group 0.45+/-0.02 (P) versus 0.78+/-0.05 (C); P < 0.05 when compared with C group. SM treatment significantly reduced MCP-1 mRNA and protein expression in balloon-injured abdominal aorta. These inhibitory effects on intimal response after balloon injury might be attributed to antioxidant capacity and cholesterol lowering effect of SM. SM treatment may offer some protection against post-angioplasty restenosis.

Saturated fats, cholesterol, and dietary compliance
Henkin, Y., D. W. Garber, et al. (1992), Arch Intern Med 152(6): 1167-74.
Abstract: BACKGROUND--Lack of response to a cholesterol-lowering diet can be caused by physiological nonresponsiveness, inadequate knowledge, or inability to change dietary habits (poor compliance). The purpose of this study was to evaluate the dietary compliance of hyperlipidemic individuals who received intensive initial dietary education and followup, and who showed an initial reduction of their plasma cholesterol levels. METHODS--One hundred five individuals with fasting cholesterol levels of 5.17 mmol/L (200 mg/dL) or greater received intensive education and follow-up on the American Heart Association Step I diet during an initial 12-week period. The participants provided 3-day dietary records every week, and fasting lipoprotein analysis was performed biweekly. Six months after termination of this period, the subjects were requested to return for a follow-up evaluation of their lipoprotein profile and dietary adherence. RESULTS--Seventy-three (70%) of the subjects returned for a follow-up evaluation of lipoprotein cholesterol levels. Of these, 42 (58%) had a 10% or greater average initial decrease in total cholesterol levels at weeks 3 and 4 ("baseline"), and they were considered to be "high responders." At the 6-month follow up, the average plasma cholesterol level in these responders remained 6.4% below that at entry level, but it had increased by 19% compared with baseline values (6.30 mmol/L 244 mg/dL vs 5.43 mmol/L 210 mg/dL, respectively). Corresponding significant increases at 6 months were found in high-density lipoprotein cholesterol (8%), low-density lipoprotein cholesterol (16%), and very-low-density lipoprotein cholesterol (66%) levels. Analysis of dietary histories revealed that dietary cholesterol and percent calories from fat increased significantly, but remained within the recommended guidelines. However, the increase in percent calories from saturated fat (from 10.0% +/- 0.5% to 14.4% +/- 1.0% mean +/- SEM) deviated markedly from these guidelines. CONCLUSIONS--The results suggest the long-term compliance to the reduction of dietary saturated fat remains a problem, even in individuals who receive intensive initial training and show an early favorable response. Follow-up evaluation of hyperlipidemic patients who are receiving dietary therapy should take into account this behavioral pattern. It remains to be determined whether continuing supervision and better nutritional labeling will facilitate dietary compliance.

Saturated fatty acid, but not cholesterol, regulates apolipoprotein AI gene expression by posttranscriptional mechanism
Srivastava, R. A. (1994), Biochem Mol Biol Int 34(2): 393-402.
Abstract: The aim of the present study was to investigate the regulation of the apoAI gene by dietary saturated fat and cholesterol. Saturated fatty acids and cholesterol raise low density- and high density lipoprotein particles in humans. Increased LDL is attributed to the down-regulation of LDL-receptor gene, but the mechanism of increased plasma HDL levels is unknown. To study the mechanism of HDL elevation by saturated fat, male rats and male mice were employed as animal models, since they also raise their plasma HDL levels when fed high lipid diets. Animals were divided in four groups and fed the following diets: control (5% corn oil); high cholesterol (0.5%); high fat (20% coconut oil); and high fat plus cholesterol diets. The high cholesterol diet did not alter plasma and HDL-cholesterol levels. However, the high fat diet increased HDL levels by 20% in rats and 55% in mice. A combination of saturated fat and cholesterol diet raised plasma HDL levels by 36 and 67% in rats and mice, respectively. Plasma apoAI levels increased parallel to HDL concentrations. Mechanism of HDL elevation by saturated fat was investigated. Hepatic and intestinal apoAI mRNA did not change with any of the test diets in mice. Rat hepatic apoAI mRNA was also unchanged by the high cholesterol diet, but was decreased on high fat and fat-cholesterol combination diets. These results suggest that transcriptional regulation of the apoAI gene was not responsible for increased plasma apoAI and HDL. The translational efficiency of apoAI on isolated polysomes was also measured, and it was found that apoAI synthesis increased about 20% on high fat and fat-cholesterol combination diets. This partially explains the elevated levels of plasma HDL. Additional regulation through impaired catabolism of HDL particles by high fat diet feeding may be another pathway for increased HDL levels. Unlike apoAI mRNA, the mRNA of other HDL apoproteins, apoAII and apoAIV, were increased by high fat and combination diet feeding. These results suggest that saturated fatty acids regulate plasma HDL levels by translational and posttranslational mechanisms.

SC-435, an ileal apical sodium co-dependent bile acid transporter (ASBT) inhibitor lowers plasma cholesterol and reduces atherosclerosis in guinea pigs
West, K. L., T. L. Zern, et al. (2003), Atherosclerosis 171(2): 201-10.
Abstract: Male Hartley guinea pigs were randomly allocated to one of four treatments, 10 guinea pigs per group, for 12 weeks. The control diet contained no ASBT inhibitor (ASBTi) or simvastatin. Low ASBTi (LowASBTi) and high ASBTi (HighASBTi) were monotherapies containing 0.03 g/100 g and 0.1 g/100 g of the ASBTi SC-435. Combination therapy (COMBO) was a combination therapy consisting of 0.03 g/100 g ASBTi and 0.05 g/100 g simvastatin. Based on food consumption, guinea pigs received 17.2 and 47.8 mg/kg per day ASBTi in the ASBTi groups or 13.7 mg/kg per day ASBTi and 21.4 mg/kg per day simvastatin in the COMBO group. The amount of cholesterol in each diet was 0.25 g/100 g. LDL cholesterol was 40 and 70% lower with the HighASBTi and COMBO treatments compared to controls. Plasma triglycerides (TG) were 70% lower with COMBO therapy while HDL cholesterol was 43-47% higher with all treatments. Hepatic free cholesterol was reduced 60-80% with all treatments. Cholesterol content in the aortic arch was reduced by 25 and 42% in the HighASBTi and COMBO groups. Fecal bile acids were increased by 2.5- and 4-fold with HighASBTi and COMBO treatments. These data suggest that the interruption in the enterohepatic circulation of bile acids by ASBTi and statin co-administration therapy cause a significant reduction in plasma cholesterol concentrations and attenuate the progression of atherosclerosis in guinea pigs.

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