Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase unmask transcriptional regulation of hepatic low-density lipoprotein receptor gene expression by dietary cholesterol.

Lopez D, Ness GC.

Department of Biochemistry and Molecular Biology, College of Medicine and the Institute for Biomolecular Science, University of South Florida, Tampa 33612, USA.

The mechanism by which dietary cholesterol regulates expression of the hepatic low-density lipoprotein (LDL) receptor was investigated. In a previous study (Arch. Biochem. Biophys. 325, 242-248, 1996), we demonstrated that dietary cholesterol reduces the rate of LDL receptor protein degradation without affecting steady-state levels of receptor protein. In view of these findings, it was expected that dietary cholesterol would decrease the rate of transcription of the hepatic LDL receptor gene, resulting in lower mRNA levels and lower rates of synthesis of LDL receptor protein. Surprisingly, neither the rate of transcription nor the level of LDL receptor mRNA was reduced in response to dietary cholesterol, even though hepatic cholesterol levels were increased twofold. This suggests that under normal conditions, dietary cholesterol does not affect LDL receptor gene expression at the level of transcription. In contrast, feeding 2% cholesterol to rats fed a diet supplemented with 0.04% lovastatin significantly decreased hepatic LDL receptor mRNA levels and transcription rates. These results suggest that lovastatin unmasks transcriptional regulation of the hepatic LDL receptor by dietary cholesterol. The levels of the mature nuclear forms of sterol response element binding proteins-1 and -2 were unaffected despite significant changes in hepatic cholesterol levels, mRNA levels, and transcription rates caused by lovastatin treatment. This suggests that the observed changes in transcription rates may not be mediated by these proteins in rat liver.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9244400&dopt=Abstract cholesterol




High fat, high cholesterol diets alter low density lipoprotein size and binding affinity in monkeys.

Hannah JS, Yamane K, Kataoka S, Anthony M, Howard BV.

Medlantic Research Institute, Washington, DC 20010, USA.

The purpose of this study was to examine the effects of various dietary fats on low density lipoprotein (LDL) binding in an in vitro system where receptor number is not regulated. Cynomolgus monkeys were fed diets containing 37% of energy from fat, with various degrees of saturation, and 0.4 mg/kcal cholesterol or low-fat (13% of energy), low cholesterol (0.03 mg/kcal) chow. Plasma LDL was isolated after 16 weeks. The fatty acid composition of LDL showed enrichment corresponding to the dietary fats consumed, and the high fat, high cholesterol diets produced marked hypercholesterolemia compared to chow feeding. Of those fed the high fat diets, monkeys fed the fish oil diet had the highest LDL cholesterol concentrations, 13.25 +/- 0.77 mmol/l, while those fed the safflower oil diet had the lowest, 7.51 +/- 3.31. LDL from chow fed monkeys had the lowest binding affinity; the Kd was 26.2 +/- 8.7 microg/ml, nearly twice that of the high fat diets (P = 0.003). No significant differences in binding were found between the different high fat diets, although there was a trend toward lower affinity in the diets enriched in polyunsaturated fat. LDL size was affected by diet with chow fed monkeys having the smallest average LDL, 259.3 +/- 1.7 A compared to the other groups (P = 0.03). Monkeys fed the fish oil diet tended to have smaller LDL, but this was not significantly different from the other high fat diets. Binding affinity was correlated with LDL size, r = 0.54, P < 0.01. LDL composition, as measured by apo B/cholesterol ratio, was altered by feeding a high fat, high cholesterol diet. The ratio was reduced in the LDL samples from monkeys fed the high fat diets compared to those fed chow, but this ratio was not significantly correlated with binding. Thus, it appears that increasing dietary fat and cholesterol intake increases LDL size and binding affinity, such that LDL metabolism may be altered independently from effects on receptor number; the type of dietary fat does not seem to influence this process when fat and cholesterol content is very high.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9247355&dopt=Abstract cholesterol




Preservation of endogenous antioxidant activity and inhibition of lipid peroxidation as common mechanisms of antiatherosclerotic effects of vitamin E, lovastatin and amlodipine.

Chen L, Haught WH, Yang B, Saldeen TG, Parathasarathy S, Mehta JL.

Department of Medicine, University of Florida College of Medicine, Gainesville 32610, USA.

OBJECTIVES: We sought to document the common mechanisms of the antiatherogenic effects of the cholesterol-lowering hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin, the dihydropyridine Ca2+ blocker amlodipine and the antioxidant vitamin E. BACKGROUND: Vitamin E, HMG-CoA reductase inhibitors and Ca2+ blockers each inhibit atherosclerosis in hypercholesterolemic animals. METHODS: New Zealand White rabbits were fed regular chow (Group A), chow with 1% cholesterol (Group B), 1% cholesterol diet plus lovastatin (Group C), 1% cholesterol diet plus vitamin E (Group D) or 1% cholesterol diet plus amlodipine (Group E) for 12 weeks. The extent of aortic atherosclerosis was measured by planimetry of the sudanophilic area. Malondialdehyde (MDA) and superoxide dismutase (SOD) in blood were measured as indexes of lipid peroxidation and antioxidant activity, respectively. RESULTS: Group A rabbits showed no atherosclerosis, whereas Group B rabbits had 17.4 +/- 9.3% (mean +/- SD) of the aorta covered with atherosclerosis, and Groups C, D and E rabbits had significantly less atherosclerosis. Plasma SOD activity was lower in Group B than in Group A (6.9 +/- 1.1 vs. 12.8 +/- 1.5 U/ml, p < 0.01) and was preserved in the groups given lovastatin, vitamin E or amlodipine with a high cholesterol diet. The serum MDA level was higher in Group B rabbits than Group A rabbits (12.1 +/- 2.6 vs. 1.2 +/- 0.1 nmol/ml, p < 0.01) and increased minimally in rabbits given lovastatin, vitamin E or amlodipine with a high cholesterol diet. In in vitro experiments, both lovastatin and amlodipine preserved SOD activity and reduced the oxidizability of low density lipoproteins by rabbit leukocytes. CONCLUSIONS: This study suggests that a reduction in lipid peroxidation and preservation of SOD may be common mechanisms of antiatherosclerotic effects of lovastatin, vitamin E and amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9247534&dopt=Abstract cholesterol




The effect of Simvastatin on the plasma antioxidant concentrations in patients with hypercholesterolaemia.

Human JA, Ubbink JB, Jerling JJ, Delport R, Vermaak WJ, Vorster HH, Lagendijk J, Potgieter HC.

Department of Chemical Pathology, University of Pretoria, South Africa.

The aim of this study was to monitor the antioxidant status of patients with hypercholesterolaemia during treatment with Simvastatin. Forty-seven patients, of whom 25 had confirmed familial hypercholesterolaemia (FH), were treated with 10 or 20 mg of Simvastatin per day for 14 weeks. As expected, total cholesterol and LDL cholesterol concentrations decreased considerably, while HDL cholesterol concentrations increased during drug treatment. In neither FH nor non-FH patients were any significant changes observed for retinol status, while plasma vitamin C concentrations were also not adversely affected by the drug therapy. In both patient groups Simvastatin therapy led to a significant decrease in plasma alpha-tocopherol (P < 0.05) concentrations, however, the alpha-tocopherol/total cholesterol ratio increased by 9.1 (P < 0.01) and 12.1% (P < 0.01) in FH and non-FH patients, respectively, during the 14-week treatment period. The coenzyme Q10/total cholesterol ratio did not change significantly in non-FH patients, but was significantly lower (P < 0.05) than the baseline ratio after 4 and 14 weeks of Simvastatin treatment in FH patients. The alpha-tocopherol/total cholesterol ratio of FH patients remained consistently and significantly lower (P < 0.01) compared with non-FH patients, indicating that LDL from the former group may be more vulnerable to free radical-mediated damage and lipid peroxidation. Our results suggest that the significant decline in circulating alpha-tocopherol and coenzyme Q10 concentrations was mainly a function of the decrease in serum total cholesterol concentrations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9247729&dopt=Abstract cholesterol




Internalized plasma membrane cholesterol passes through an endosome compartment that is distinct from the acid vesicle-lysosome compartment.

Porpaczy Z, Tomasek JJ, Freeman DA.

Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.

Cholesterol from the plasma membrane of MA-10 Leydig tumor cells is internalized into the cell and either esterified or used as substrate for steroid hormone synthesis. In the present studies we show that chloroquine and sphinganine cause LDL cholesterol and cholesteryl esters to accumulate in the cells. A lysosome fraction contained the excess cholesterol and cholesteryl esters. Both inhibitors blocked the conversion of plasma membrane cholesterol into intracellular cholesteryl esters and caused dose-dependent inhibition of dibutyryl-cAMP-stimulated progesterone synthesis. Radiolabeled cholesterol applied to the plasma membrane of MA-10 cells accumulated in the lysosome fraction of chloroquine and sphinganine-treated cells. Evidence that these inhibitors did not require the Golgi was provided by experiments using brefeldin A. Experiments utilizing a fluorescent cholesterol analogue and a lysosomal marker indicated that cholesterol entered the cells in structures that were different than the acidic vesicle-lysosome compartment. Consistent with this observation was the observation that the peak fluorescence fractions of cells subjected to density gradient centrifugation was of lower density than the lysosome fraction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9260888&dopt=Abstract cholesterol




[Risk of cardiovascular complications in patients with type II diabetes mellitus in relation to serum triacylglycerols]

[Article in Slovak]

Haban P.

Klinicke oddelenie Vyskumneho ustavu vyzivy v Bratislave, Slovakia.

BACKGROUND: The importance of serum triacylglycerols (TG) as a risk factor of cardiovascular complications in non-insulin-dependent diabetes mellitus (NIDDM) patients has been emphasized in recent studies. OBJECTIVES: In the study of our group of NIDDM patients with and without coronary artery disease (CAD), it has been expedient to follow: 1. the difference in their serum TG, VLDL lipoprotein, total, HDL and LDL cholesterol levels, 2. dependence of other parameters on TG, 3. to answer the question as to what extent the lowering of TG in NIDDM patients is expected to be decreasing the risk of CAD. METHODS: The investigated groups included the total of 39 NIDDM out-patients; 20 with manifest signs of CAD. The lipoproteins were measured using the BIO-LACHEMAR kits. MAIN RESULTS AND CONCLUSIONS: In CAD group, the serum TG and VLDL were significantly increased, HDL cholesterol being lower (p < 0.01, p < 0.01, p < 0.02, respectively). The TG-to-HDL cholesterol, TG-to-total cholesterol ratios and atherogenic index (= total cholesterol-to-HDL cholesterol ratio) were in the CAD group also significantly higher (p < 0.02, p < 0.02 and p < 0.002, respectively). Furthermore, the serum TG was positively correlated with the atherogenic index and LDL (p < 0.001 and p < 0.05; r = 0.603 and r = 0.397, respectively). The logarithm of TG was a strong positive correlate of the total cholesterol (p < 0.001; r = 0.584). On the other hand, the serum TG was negatively correlated with HDL cholesterol (p < 0.005; r = -0.466). When logarithm of TG was taken, the statistical significance of all these correlations was even higher. The serum TG levels were significantly higher in patients with CAD. (Tab. 2, Fig. 7, Ref. 10.)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9264821&dopt=Abstract cholesterol




Effects of hypercholesterolemia on the contractions to angiotensin II in the isolated aorta and iliac artery of the rabbit: role of arachidonic acid metabolites.

Dam JP, Vleeming W, Riezebos J, Post MJ, Porsius AJ, Wemer J.

Utrecht University, Faculty of Pharmacy, Department of Pharmacoepidemiology & Pharmacotherapy, The Netherlands.

The aim of this study was to investigate the effect of hypercholesterolemia on the angiotensin II-induced contractions in the isolated aorta and iliac artery of the rabbit, with respect to the role of arachidonate metabolites. Furthermore, the effect of the angiotensin-converting enzyme inhibitor ramipril was studied on the responses to angiotensin II in the cholesterol-fed rabbit. After 12 weeks of cholesterol diet (0.3%), endothelium-dependent relaxations to acetylcholine were significantly fewer compared with control (30.2 +/- 5.9% vs. 73.0 +/- 1.7%) in the aorta but not in the iliac artery of the rabbit. The angiotensin II- and methoxamine-induced contractions were also significantly lower compared with control in the aorta (101.4 +/- 6.7% vs. 60.9 +/- 4.2% and 160.2 +/- 5.7% vs. 135.8 +/- 8.0%, respectively) but not in the iliac artery. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) selectively attenuated the angiotensin II-induced contractions in rabbit aortic rings from the control group only in the presence of the endothelium, whereas it had no effect on the responses to angiotensin II in the cholesterol group (with or without endothelium). In the iliac artery, NDGA inhibited the responses to angiotensin II in both the control and cholesterol groups. Treatment with ramipril (0.33 mg/kg/day) significantly improved the maximal angiotensin II-induced contraction in the aorta of rabbits fed a cholesterol diet for 16 weeks to 61.0 +/- 7.3% (vs. 32.7 +/- 9.0% in the cholesterol group). We conclude that hypercholesterolemia leads to a reduction of angiotensin II-induced contractions in the aorta and not in the iliac artery of the rabbit. This reduction might be related to loss of endothelium-dependent lipoxygenase products and is partially reversed by ramipril.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9268230&dopt=Abstract cholesterol




[Pattern of the distribution of total cholesterol and cHDL cholesterol Spanish children and adolescents: RICARDIN Study]

[Article in Spanish]

Brotons Cuixart C, Gabriel Sanchez R, Muniz Garcia J, Ribera Sole A, Malaga Guerrero S, Saenz Aranzubia PE, Diaz Gonzalez-Blanco MT, Sanchez Bayle M, Sandin Dominguez M, Bosch Gimenez V, Gorostiza Garai E, Labarthe DR, Fernandez-Cruz A, Ricardin P.

Unidad de Epidemiologia Clinica. Servicio de Cardiologia. Hospital Universitario Vall d'Hebron. Barcelona.

BACKGROUND: The RICARDIN Study multicenter study of cardiovascular risk factors in children and adolescents has described the standards of normality of blood cholesterol levels in the Spanish school population. The objective of the present study was to compare mean values of cholesterol between different regions of Spain, and to compare the global mean with a pool international study. Also, the pattern of total cholesterol and cHDL by age and sex using mathematical model is described, and comparison with two international studies carried out in USA and Japan is performed. SUBJECTS AND METHODS: 10,683 children aged 6 to 18 were selected from 7 different Spanish provinces (Madrid, Vizcaya, Lugo, Badajoz, Murcia, Asturias and Barcelona). Blood samples were obtained by capilar puncture (Reflotron). RESULTS: Mean values of total cholesterol was different among provinces, and globally, were lower than the international pooled population, although the pattern observed in each population was very similar. Total cholesterol curve for Spanish boys showed a curvilinear trend that can be estimated through a cubic function that explains 89% of observed data, while for girls the best estimate was obtained through an inverse function (R2 = 0.40). cHDL for boys showed a cubic function as the best estimate (R2 = 0.90), while for girls the best estimate was obtained through a quadratic function (R2 = 0.59). CONCLUSIONS: There are important physiological variations of total cholesterol level by age and sex in children and adolescents. The pattern of cholesterol does not follow a linear model but a curvilinear one, that need to be considered in clinically assessing individual determinations of cholesterol, since highest percentiles can vary by age and sex.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11141413&dopt=Abstract cholesterol




Passive cigarette smoking and reduced HDL cholesterol levels in children with high-risk lipid profiles.

Neufeld EJ, Mietus-Snyder M, Beiser AS, Baker AL, Newburger JW.

Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass 02115, USA. neufeld a1.tch.harvard.edu

BACKGROUND: HDL cholesterol levels are known to be lower in smokers than in nonsmokers. Previous studies have demonstrated an association of decreased HDL cholesterol with passive smoking in children but have not adjusted for potential confounding factors. METHODS AND RESULTS: In a cross-sectional, pilot-scale study, we examined the relationship of HDL cholesterol levels to passive smoking in children and adolescents referred to a tertiary hyperlipidemia clinic. Eligibility criteria included (1) first visit to a lipid clinic, (2) LDL cholesterol >95th percentile for age or HDL cholesterol <5th percentile, (3) age between 2 and 18 years, and (4) absence of secondary causes of hyperlipidemia. Sociodemographic information, diet record, medical history, and fasting lipid profiles were obtained. Of 109 eligible patients, 103 (94%) were studied. Twenty-seven percent came from households with cigarette smokers. HDL cholesterol levels were 38.7+/-1.2 mg/dL (mean+/-SEM) in passive smokers versus 43.6+/-1.2 mg/dL in children without smoke exposure (P=.005). Smoking exposure was not significantly associated with other lipid values. The effect of smoking on HDL cholesterol was minimally affected by potential confounders. In multivariate regression adjusting for body mass index, age, sex, exercise, and dietary fat intake, passive smoking remained a significant risk factor for decreased HDL cholesterol (P=.012). CONCLUSIONS: Mean HDL cholesterol levels are lower in dyslipidemic children from households with smokers than in those without household smoke exposure. Passive smoking may worsen the risk profile for later atherosclerosis among high-risk young persons.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9315524&dopt=Abstract cholesterol