The interrelationship among tobacco consumption, high-density lipoprotein cholesterol and leukocyte counts.

Celada MM, Reguero JR, Cubero GI.

Servicio de Cardiologia, Hospital Universitario Central de Asturias, Oviedo, Spain.

BACKGROUND: Tobacco consumption is a major cardiovascular risk factor that has been related to changes in lipoprotein levels and in the leukocyte count. OBJECTIVE: To investigate the interrelationship among leukocytes, high-density lipoprotein (HDL) cholesterol levels and tobacco consumption. METHODS: In total 1022 healthy male miners aged 40.5+/-8 years (mean+/-SD) were evaluated consecutively during the period 1993-1994. We evaluated the smoking history of all of the subjects by means of a structured questionnaire. After the subject had fasted for 12 h we extracted blood samples by venepuncture. Plasma concentrations of HDL were determined enzymatically (by the CHOD-PAP method) and the leukocyte count was determined with an automatic analyser. Statistical analysis was performed using analysis of variance for the mean differences and the Pearson and stepwise tests to determine correlations. RESULTS: The leukocyte count was significantly lower (8.014+/-2.327/mm3, P < 0.05) in those subjects with levels of HDL cholesterol equal to or greater than 0.9 mmol/l in comparison with that in those with HDL cholesterol levels lower than 0.9 mmol/l (8.450+/-2.375/mm3). Leukocyte counts were correlated directly to tobacco consumption (r= 0.3119, P < 0.01) and inversely to H DL cholesterol levels (r = -0.1513, P < 0.01). HDL cholesterol levels were lower in smokers (1.15+/-0.31 mmol/l) and these differences were significant with respect to the levels in non-smokers (1.22+/-0.30 mmol/l, P<0.05) but not with respect to those in former smokers (1.21+/-0.39 mmol/l). The leukocyte count was significantly greater in smokers (8.963+/-2.428/mm3, P<0.05) than it was in former smokers (7.041+/-1.698/mm3) and in non-smokers (6.793+/-1.599/mm3). CONCLUSIONS: The results of this study indicate that tobacco consumption is associated with lower HDL cholesterol levels and higher leukocyte counts. Leukocyte counts correlate positively to tobacco consumption and inversely to HDL cholesterol levels. Subjects with HDL cholesterol levels lower than 0.9 mmol/l present with leukocyte counts higher than those found in those with HDL cholesterol values equal to or greater than 0.9 mmol/l.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9477206&dopt=Abstract cholesterol




Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes.

Clee SM, Kastelein JJ, van Dam M, Marcil M, Roomp K, Zwarts KY, Collins JA, Roelants R, Tamasawa N, Stulc T, Suda T, Ceska R, Boucher B, Rondeau C, DeSouich C, Brooks-Wilson A, Molhuizen HO, Frohlich J, Genest J Jr, Hayden MR.

Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.

We and others have recently identified mutations in the ABCA1 gene as the underlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced cholesterol efflux. We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL cholesterol (HDL-C) and increased triglycerides. Age is an important modifier of the phenotype in heterozygotes, with a higher proportion of heterozygotes aged 30-70 years having HDL-C greater than the fifth percentile for age and sex compared with carriers less than 30 years of age. Levels of cholesterol efflux are highly correlated with HDL-C levels, accounting for 82% of its variation. Each 8% change in ABCA1-mediated efflux is predicted to be associated with a 0.1 mmol/l change in HDL-C. ABCA1 heterozygotes display a greater than threefold increase in the frequency of coronary artery disease (CAD), with earlier onset than unaffected family members. CAD is more frequent in those heterozygotes with lower cholesterol efflux values. These data provide direct evidence that impairment of cholesterol efflux and consequently reverse cholesterol transport is associated with reduced plasma HDL-C levels and increased risk of CAD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11086027&dopt=Abstract cholesterol




Changes in cultured arterial smooth muscle cells isolated from chicks upon cholesterol feeding.

Carazo A, Alejandre J, Diaz R, Rios A, Castillo M, Linares A.

Department of Biochemistry, Faculty of Sciences, University of Granada, Spain.

We have developed cultures of smooth muscle cells (SMC) isolated from arterial hypercholesterolemic chicks (cholesterol-SMC). These cultures are suitable for the study at the molecular level of the changes in arterial SMC induced by a cholesterol diet. By using a strong dose of cholesterol (5%) for 10 d, we obtained very proliferative SMC which became foam cells after 30 d in culture. On the other hand, SMC cultures isolated from control-fed chicks had a lower growth rate than the SMC ones under the same culture conditions. DNA synthesis was fourfold greater in cholesterol-SMC than in control-SMC cultures. Intracellular cholesterol concentrations were the same in both cholesterol and control SMC during the first 14 d of culture but afterward increased in differing ways: after 20 d of culture the cholesterol-SMC increased their cholesterol content to double the control. We give here the results obtained from transmission electron microscopy, lipid analysis, proliferation studies, DNA, RNA and protein synthesis, and then discuss their implications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9507240&dopt=Abstract cholesterol




Fermentation products of sugar-beet fiber by cecal bacteria lower plasma cholesterol concentration in rats.

Hara H, Haga S, Kasai T, Kiriyama S.

Laboratory of Nutritional Biochemistry, Department of Bioscience and Chemistry, Faculty of Agriculture, Hokkaido University, Sapporo 060, Japan.

Plasma cholesterol concentration is reduced by feeding some dietary fibers but the mechanism is not fully understood. We examined whether cecal fermentation products are involved in lowering plasma cholesterol by feeding rats a highly fermentable sugar-beet fiber (SBF) in four separate experiments. These were designed to investigate the effects on plasma cholesterol of oral ingestion of fermentation products on plasma cholesterol, the effects of the products in comparison with that of a short-chain fatty acid (SCFA) mixture, effects of individual SCFA and effects of alteration of energy and nitrogen ratio in the diet by the addition of the SCFA mixture. Cecal contents of rats were cultured with SBF by using a jar fermenter under anaerobic conditions, and the supernatant from the culture medium, containing fermentation products of SBF, was collected and freeze-dried before feeding to rats. Yield of fermentation products as dry weight from the fiber was 80-90%. In rats fed a diet containing fermentation products (80 g/kg diet), plasma cholesterol concentrations were lower than in rats of the fiber-free group 3, 7 and 14 d after feeding the test diet. Major SCFA in the fermentation products were sodium salts of acetic, propionic and butyric acids. Plasma cholesterol concentration in rats fed the diet containing a mixture of equal amounts of the three SCFA salts (66 g/kg diet) as the fermentation products diet was also lower than that in the fiber-free group and was not different from those in rats fed SBF (100 g/kg diet) and the fermentation products. In rats fed an acetate-containing diet but not in rats fed diets without acetate, plasma cholesterol was significantly lower than in the fiber-free group. In conclusion, absorption of SCFA from cecal fermentation products lowers plasma cholesterol. Acetate, and not propionate, may be responsible for lowering plasma cholesterol concentration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9521629&dopt=Abstract cholesterol




Silymarin inhibits the development of diet-induced hypercholesterolemia in rats.

Krecman V, Skottova N, Walterova D, Ulrichova J, Simanek V.

Institute of Medical Chemistry, Medical Faculty, Palacky University, Olomouc, Czech Republic.

To study the ability of silymarin, a standardized mixture of antioxidant flavonolignans from the medicinal plant Silybum marianum, and of silybin, the main flavonolignan of silymarin, to inhibit the development of diet-induced hypercholesterolemia the rats were fed high cholesterol diet (HCD). Silymarin or silybin were given as dietary supplements, and their influences on serum cholesterol levels were compared to those of probucol, an antioxidant hypocholesterolemic drug. Anticholesterolemic effect of silymarin was parallel to that of probucol, and dose-dependent at dietary drug concentrations of 0.1-0.5-1.0% (w/w). However, in contradistinction to probucol, silymarin caused an increase in high density lipoprotein (HDL)-cholesterol and a decrease in liver cholesterol content, changes considered to be of benefit. In addition to its anticholesterolemic effect silymarin partially prevented the HCD-induced decrease in liver reduced glutathione, an endogenous antioxidant. Silybin was not so effective as silymarin suggesting that either other constituent(s) of silymarin may be responsible for its anticholesterolemic effect or the bioavailability of silybin alone might be lower than that of silybin as a compound of silymarin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9525106&dopt=Abstract cholesterol




Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption.

Rosenblum SB, Huynh T, Afonso A, Davis HR Jr, Yumibe N, Clader JW, Burnett DA.

Department of Discovery Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA. stuart.rosenblum spcorp.com

(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)- (4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9526571&dopt=Abstract cholesterol




Cholesterol lowering in pigs through enhanced bacterial bile salt hydrolase activity.

De Smet I, De Boever P, Verstraete W.

Laboratory of Microbial Ecology, Faculty of Agricultural and Applied Biological Sciences, University Gent, Belgium.

The effect of feeding live Lactobacillus reuteri cells containing active bile salt hydrolase (BSH) on plasma cholesterol levels was studied in pigs. During an experiment lasting 13 weeks, twenty pigs were fed on a high-fat, high-cholesterol, low-fibre for the first 10 weeks, and a regular pig diet for the last 3 weeks. One group of animals received, twice daily, 11.25 (SD 0.16) log10 colony forming units of the potential probiotic bacteria for 4 weeks (from week 3 until week 7). From week 8 onwards, the treated group was again fed on the same diet as the control group without additions. The total faecal Lactobacillus counts were only significantly higher in the treated pigs during the first 2 weeks of L reuteri feeding. Based on limited data, it was suggested that the administered Lactobacillus species had caused a temporary shift within the indigenous Lactobacillus population rather than permanently colonizing the intestinal tract. The probiotic feeding brought about significant lowering (P < or = 0.05) of total and LDL-cholesterol concentrations in the treated pigs compared with the control pigs, while no change in HDL-cholesterol concentration was observed. The data for faecal output of neutral sterols and bile salts were highly variable between the animals of each group, yet they indicated an increased output in the treated pigs. Although the blood cholesterol levels went up in both groups during the 3 weeks following the Lactobacillus administration period, significantly lower serum total and LDL-cholesterol levels were observed in the treated pigs. During the final 3 weeks of normalization to the regular diet, cholesterol concentrations significantly decreased in both animal groups and the differences in total and LDL-cholesterol concentrations between the groups largely disappeared.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9536863&dopt=Abstract cholesterol




Similar response to simvastatin in patients heterozygous for familial hypercholesterolemia with mRNA negative and mRNA positive mutations.

Sijbrands EJ, Lombardi MP, Westendorp RG, Leuven JA, Meinders AE, Van der Laarse A, Frants RR, Havekes LM, Smelt AH.

Department of General Internal Medicine, Medical Faculty, Leiden, The Netherlands. nrexpert euronet.nl

In patients heterozygous for familial hypercholesterolemia, the low-density lipoprotein (LDL) cholesterol lowering effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors may depend on the nature of the mutation in the LDL receptor gene. To test this hypothesis, we compared the response to simvastatin, 20 mg daily for 9 weeks, between heterozygous carriers of functionally different classes of mutations, i.e. mRNA negative or mRNA positive mutations. Out of 116 consecutive, unrelated patients with familial hypercholesterolemia, 27 patients were selected for molecular analyses: 14 patients with mRNA negative and 13 with mRNA positive mutations. Before simvastatin treatment, patients with mRNA negative mutations had higher levels of LDL cholesterol, lower levels of high-density lipoprotein (HDL) cholesterol and significantly more often tendon xanthomas, compared to patients with mRNA positive mutations. Simvastatin reduced the mean fasting LDL cholesterol levels to a similar percentage in the mRNA negative and mRNA positive patients (37, 36%, respectively, 95% CI of difference--8 to 5%, P = 0.2). This effect was similar to the 37% decrease observed in our total series of patients with familial hypercholesterolemia (n = 116). The increase in mean concentration of HDL cholesterol was greater in the mRNA negative group than in the mRNA positive group (16, 0%, respectively, 95%, CI of difference 8-25%, P = 0.002) independent of the response of total triglycerides to simvastatin. The percentage LDL cholesterol lowering response varied among multiple carriers of the same mutation, even in the case of mRNA negative mutations. We conclude that the percentage LDL lowering response to simvastatin treatment was similar in patients with mRNA negative and mRNA positive mutations. Moreover, variation of this response within multiple carriers of the same mutation suggests an influence of additional factors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9543095&dopt=Abstract cholesterol




Prebeta-1 HDL in plasma of normolipidemic individuals: influences of plasma lipoproteins, age, and gender.

O'Connor PM, Zysow BR, Schoenhaus SA, Ishida BY, Kunitake ST, Naya-Vigne JM, Duchateau PN, Redberg RF, Spencer SJ, Mark S, Mazur M, Heilbron DC, Jaffe RB, Malloy MJ, Kane JP.

Cardiovascular Research Institute, University of California-San Francisco, 94143, USA.

Prebeta-1 HDL is a molecular species of plasma HDL of approximately 67 kDa mass that contains apolipoprotein A-I, phospholipids, and unesterified cholesterol. It participates in a cyclic process involved in the retrieval of cholesterol from peripheral tissues. In this cycle, unesterified cholesterol from cells is incorporated into prebeta-1 HDL, providing a substrate for esterification of cholesterol by lecithin:cholesterol acyltransferase. Prebeta-1 HDL then becomes incorporated into larger HDL species of alpha mobility as esterification proceeds and is regenerated during the transfer of cholesteryl esters from alpha HDL particles to acceptor lipoproteins. Thus the steady state level of prebeta-1 HDL in plasma reflects the relative efficiencies of the major metabolic processes involved in its generation and removal. We have used an isotope dilution technique to measure prebeta-1 HDL levels in the plasmas of 136 normolipidemic individuals (46 M, 90 F). The mean absolute concentration of prebeta-1 HDL as apolipoprotein A-I was 68 +/- 40 microg/ml for women, and 84 +/- 49 m/ml for men. Prebeta-1 HDL represented 5.5 +/- 3.3% of total apolipoprotein A-I in women, and 7.2 +/- 4.0% in men. The distributions of both absolute and percent prebeta-1 HDL are highly asymmetric, with skew toward higher values. However, the skew appears not to be attributable to either plasma cholesterol or triglyceride levels which are also skewed in population samples. The percent prebeta-1 HDL was negatively correlated with HDL cholesterol levels (P < 0.0001), whereas absolute levels of prebeta-1 HDL were positively correlated with apolipoprotein A-I and negatively correlated with HDL cholesterol (P, for both, < 0.0001). Multiple linear regression analysis revealed effects of age and gender, but no association with lipoprotein fractions other than HDL. Lower levels of prebeta-1 HDL were associated with female gender in all models.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9548598&dopt=Abstract cholesterol