Total and HDL cholesterol and risk of stroke. EUROSTROKE: a collaborative study among research centres in Europe.BACKGROUND: Controversy remains on the relation between serum lipids levels and stroke risk. This paper investigated the association of total and HDL cholesterol level to fatal and non-fatal, and haemorrhagic and ischaemic stroke in four European cohorts participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European cohort studies on incidence and risk factors of stroke. EUROSTROKE is designed as a nested case-control study. For each stroke case, two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. At present, data on stroke and risk factors were available from cohorts in Cardiff (84 cases), Kuopio (74 cases), Rotterdam (157 cases), and Novosibirsk (79 cases). RESULTS: Pooled analyses showed no significant association between total cholesterol and risk of stroke (odds ratio for increase of 1 mmol/l in cholesterol of 0.98 (95% CI 0.88 to 1.09)). Analyses for haemorrhagic stroke and cerebral infarction revealed odds ratios of 0.80 (95% CI 0.61 to 1.05) and 1.06 (95% CI 0.94 to 1.19), respectively. The association of HDL cholesterol to stroke was different in men compared with women. In men, there was a general trend towards a lower risk of stroke with an increase in HDL (odds ratio per 1 mmol/l increase in HDL cholesterol 0.68 (95% CI 0.40 to 1.16)). In women, however, an increase in HDL was associated with a significant increased risk of non-fatal stroke and of cerebral infarction (odds ratios of 2.46 (95% 0.1.20 to 5.04) and 2.52 (95% CI 1.15 to 5.50), respectively. The difference between men and women in the association of HDL with stroke seemed to differ mainly in smokers and never smokers, but not among ex smokers. CONCLUSION: This analysis of the EUROSTROKE project could not disclose an association of total cholesterol with fatal, non-fatal, haemorrhagic or ischaemic stroke. HDL cholesterol however, seemed to be related to stroke differently in men than in women.

Characteristics and regulation of bile salt synthesis and secretion by human hepatoma HepG2 cells.Bile salt uptake, synthesis and secretion by the human hepatoma-derived cell line HepG2 were studied. The cells transported and secreted bile salts largely by means of passive mechanisms. The cells synthesized and secreted the normal human primary bile salts. The ratio of cholate to chenodeoxycholate was 1.5:1. The degree of conjugation, about 35%, was lower than normal, and the glycine-to-taurine ratio was abnormal (4.5:1). This was not due to amino acid deficiency in the medium. Contrary to the report of others, little 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid was secreted. This was confirmed by gas chromatography-mass spectrometry. The total rate of synthesis was about 33% that of normal liver. The specific activity of bile salts synthesized from [3H]mevalonate was about 20 times higher than that of the cellular cholesterol derived from the same precursor. The regulation of bile salt synthesis by two compounds that could alter the precursor pool of cholesterol was studied. After a 24-hr incubation in serum-free medium, the compound 25(OH)cholesterol inhibited the rate of bile salt synthesis compared with control values, possibly by depleting the intracellular free cholesterol pool. Surprisingly, however, progesterone, which inhibits cholesterol esterification and should have expanded this pool, also inhibited bile salt synthesis under those conditions. The effect of these compounds on the level of mRNA for cholesterol 7 alpha-hydroxylase was also determined by Northern-blot analysis. The cholesterol 7 alpha-hydroxylase mRNA was 3.7 kb, similar to that in the rat. The incubation of cells in 25(OH)cholesterol or progesterone, as above, resulted in a decreased level of mRNA. The reduction was proportional to the reduction in bile salt synthesis, suggesting that these compounds act at a pretranslational level. Taken together, these results suggest that our particular subclone of HepG2 cells will be useful for studies of the regulation of bile salt synthesis, but not of transport, by human liver-derived tissue.

Declining levels of total serum cholesterol in adult New Zealanders.AIM: To measure the average serum concentration of total cholesterol and high density lipoprotein cholesterol in a representative sample of New Zealanders. METHODS: Serum total and high density lipoprotein cholesterol levels were measured in a representative sample of 1,412 men and 1,741 :women aged 15 years or older who participated in the National Nutrition Survey (1997) of New Zealanders. RESULTS: The average serum total cholesterol concentration in men was the same as in women (5.7 mmol/L); however, younger women (44 years and under) tended to have lower levels and older women (55 years and over) higher levels of total cholesterol than men. Women in all age groups had higher average levels of high density lipoprotein cholesterol (1.4 mmol/L) than men (1.2 mmol/L). Ethnic differences were apparent with Maori men having significantly higher average levels of total cholesterol than their New Zealand European counterparts. CONCLUSIONS: Mean serum total cholesterol concentration in women has declined by 0.3 mmol/L from 6.0 mmol/L (p<0.05) since the previous representative survey of New Zealanders (Life in New Zealand Survey, 1989), but by only 0.1 mmol/L in men, despite a similar reduction amongst men and women in the proportion of dietary energy derived from total and saturated fat. It is possible that weight gain in men and women during the last nine years is having a differential effect on serum cholesterol concentrations.

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

Quality of treatment in hypercholesterolemia in ambulatory patientsIn 1989 serum cholesterol was determined as a routine procedure in 534 consecutive patients. The response of the physicians to elevated cholesterol levels and factors associated with a treatment decision were analyzed. A follow-up was obtained in treated patients after at least one year. 105 patients (20%) had hypercholesterolemia, 84 of whom were available for evaluation; only in 34 (40%) was treatment initiated. Patients were more likely to be treated (p less than 0.05) if they had cholesterol greater than 1 mmol/l above normal, if they were between 41 and 50 years old, and if cholesterol had been determined at the physician's special request. The decision to treat was not influenced by sex, presence of further risk factors or by manifest atherosclerosis. After one year, 11 of 26 patients were still well controlled and treated. Their mean cholesterol level was significantly lower as compared to pretreatment levels. We conclude that initial as well as long-term management of patients with hypercholesterolemia should be improved.

Impact of obesity on lipid profiles in middle-aged women.OBJECTIVE: The goal of the study was to analyze the impact of overweight on lipid and apolipoprotein A-I and B (apoA-I, apoB) profiles in the women's blood serum. MATERIAL AND METHODS: Seventy-five women without any symptoms of Coronary Heart Disease were examined. Women were divided into two groups: those with normal weight and the body mass index (BMI) less than 25 (n=34, BMI 22.3+/-1.5; mean age 62+/-8.7 years) and overweight women (n=41, BMI 29.7+/-3.7; mean age 59+/-9.4). Weight and height were measured and blood serum concentrations of total cholesterol, high-density lipoprotein cholesterol, and triglycerides were determined after an overnight fasting. In the same serum samples the levels of apoA-I and B were measured using monoclonal antibodies against apo (Spinreact AA, Sant Esteve De Bas, Spain) by the immunoturbidimetry method. The serum samples were kept frozen at -40 degrees C until used. RESULTS: Total cholesterol and triglycerides levels were similar in the healthy and the overweight women groups (6.49+/-1.25 vs 6.52+/-1.18 mmol/l; p>0.05 and 1.21+/-0.71 vs 1.41+/-0.98 mmol/l; p>0.05, respectively). The concentrations of high-density lipoprotein cholesterol and apoA-I were significantly higher in the normal weight women compared to the overweight women (1.84+/-0.52 vs 1.40+/-0.29 mmol/l, p<0.001 and 1.40+/-0.26 vs 1.24+/-0.23 g/l, p<0.01, respectively). The level of apoB was significantly higher in the overweight female group compared to normal weight women (0.83+/-0.21 vs 0.74+/-0.18 g/l, p=0.049). The apoB/A-I ratio was significantly lower in the normal weight group than in the overweight group (0.055+/-0.15 vs 0.70+/-0.22; p<0.001). Moderate to strong correlations between apoA-I and high-density lipoprotein cholesterol concentrations were found in both groups (r=0.41, p<0.01 in the control female group and r=0.59, p<0.0001 in the overweight group, respectively). A similar level of correlation between apoB and total cholesterol was established in both groups (r=0.54, p<0.0005 and r=0.67, p<0.0001, respectively). CONCLUSION: Obesity in middle-aged women is associated with a significant decrease in serum high-density lipoprotein cholesterol and apoA-I levels, a significant increase in apoB and apoB/A-I ratio, even if serum total cholesterol and triglycerides concentrations are unaltered. Changes of the lipid profile in obese women are indicative of a higher risk of Coronary Heart Disease.

Reduction of serum cholesterol and hypercholesterolemic atherosclerosis in rabbits by secoisolariciresinol diglucoside isolated from flaxseed.BACKGROUND: Secoisolariciresinol diglucoside (SDG) is a plant lignan isolated from flaxseed. Lignans are platelet-activating factor-receptor antagonists that would inhibit the production of oxygen radicals by polymorphonuclear leukocytes. SDG is an antioxidant. Antioxidants studied thus far are known to reduce hypercholesterolemic atherosclerosis. The objective of this study was to determine the effect of SDG on various blood lipid and aortic tissue oxidative stress parameters and on the development of atherosclerosis in rabbits fed a high-cholesterol diet. METHODS AND RESULTS: Rabbits were assigned to 4 groups: group 1, control; group 2, SDG control (15 mg. kg body wt-1. d-1 PO); group 3, 1% cholesterol diet; and group 4, same as group 3 but with added SDG (15 mg. kg body wt-1. d-1 PO). Blood samples were collected before (time 0) and after 4 and 8 weeks of experimental diets for measurement of serum triglycerides, total cholesterol (TC), and LDL, HDL, and VLDL cholesterol (LDL-C, HDL-C, and VLDL-C). The aorta was removed at the end of the protocol for assessment of atherosclerotic plaques; malondialdehyde, an aortic tissue lipid peroxidation product; and aortic tissue chemiluminescence, a marker for antioxidant reserve. Serum TC, LDL-C, and the ratios LDL-C/HDL-C and TC/HDL-C increased in groups 3 and 4 compared with time 0, the increase being smaller in group 4 than in group 3. Serum HDL-C decreased in group 3 and increased in group 4 compared with time 0, but changes were lower in group 3 than in group 4. SDG reduced TC and LDL-C by 33% and 35%, respectively, at week 8 but increased HDL-C significantly, by>140%, as early as week 4. It also decreased TC/LDL-C and LDL-C/HDL-C ratios by approximately 64%. There was an increase in aortic malondialdehyde and chemiluminescence in group 3, and they were lower in group 4 than in group 3. SDG reduced hypercholesterolemic atherosclerosis by 73%. CONCLUSIONS: These results suggest that SDG reduced hypercholesterolemic atherosclerosis and that this effect was associated with a decrease in serum cholesterol, LDL-C, and lipid peroxidation product and an increase in HDL-C and antioxidant reserve.

Effects of passive exposure to tobacco, socioeconomic status and a family history of essential hypertension on lipid profiles in children.There is abundant evidence that the atherosclerotic process begins in childhood. Dyslipidemia is a major risk factor for atherosclerosis in adults and children. In the present study, we measured serum lipoprotein concentrations in 194 healthy children aged between 4 to 14 years. Children were grouped according to the socioeconomic status of the families, family history of essential hypertension and passive tobacco exposure. The values of total cholesterol, low density lipoprotein cholesterol and the ratio of total cholesterol/high density lipoprotein cholesterol in the low socioeconomic group were found to be significantly higher than the values obtained for the middle-high socioeconomic group. The values of total cholesterol, low density lipoprotein cholesterol, the ratio of total cholesterol/high density lipoprotein cholesterol and low density lipoprotein cholesterol/high density lipoprotein cholesterol in the passive smoker group were found to be significantly higher than those of the nonsmoker group. But, the socioeconomic level in the passive smoker group was found to be significantly lower than that of the nonsmoker group, and therefore, the impact of passive smoking on the serum lipids in children was related to socioeconomic status. A significant difference in terms of blood lipid fractions between the groups with and that without a family history of essential hypertension was not found. These results suggest that passive smoking and lower socioeconomic status are important risk factors for cardiovascular heart disease, while a positive family history of essential hypertension is not an important risk factor.

Occupational exposure to lead and blood cholesterol in glucose-6-phosphate dehydrogenase deficient and normal subjects.The effect of chronic lead poisoning on blood cholesterol levels of 148 patients, admitted to the Institute of Occupational Medicine of the University of Cagliari (Italy), was studied in connection with the genetic pattern of Glucose-6-Phosphate Dehydrogenase (G6PD) activity. The erythrocyte G6PD activity of twenty-six patients was genetically deficient. Multiple regressions were elaborated including the following in the model as independent variables: age, Quetelet index and blood lead or urinary lead in the 24 hours following 15 mg/Kg of i.v. calcium ethylen-diamine-tetracetate (EDTA) (PbUEDTA), expressed as a ratio with body weight (PbUEDTA/Kg). Dependent variables were alternatively, total cholesterol, cholesterol esters, LDL and HDL cholesterol. The analysis showed that G6PD deficient subjects have generally lower intercepts, but only for HDL the difference approached the statistical significance. Lead poisoning affected blood cholesterol of G6PD deficient subjects differently from normal ones: while total cholesterol and LDL tended to decrease in both, positive slopes were observed for cholesterol esters in G6PD deficient and for HDL in G6PD normal subjects.

A mixture of organisms affects cholesterol metabolism together with rat cecal flora.The effects of a mixture of organisms on cecal fermentation and cholesterol metabolism in sham-operated and cecectomized rats were investigated. Male F344 rats, allocated into four groups: cecectomized rats fed a mixture of organisms (CEMO), cecectomized rats fed rice bran (CERB), sham-operated rats fed a mixture of organisms (SHMO), and sham-operated rats fed rice bran (SHRB) for 4 weeks. The diets had 0.5% cholesterol and 0.125% sodium cholate added. There were no significant differences in the body weight gain and food intake among the groups. The cecal pH in the SHMO group was significantly lower than that in the other groups. The total cholesterol and (VLDL + IDL + LDL)-cholesterol concentrations in serum were significantly lower in the SHMO group than that in the SHRB group, and the triacylglycerol concentration in the sham-operated rats tended to decrease compared to the cecectomized rats. The fecal cholesterol excretion in the CERB group was higher than that in the other groups, and that in the SHMO group was significantly higher than in the SHRB group. The acetic acid, propionic acid, n-butyric acid, and total short-chain fatty acid concentrations in the cecum contents were significantly higher in the SHMO group than those in the other groups. Streptococcus, Bifidobacterium, and Lactobacillus in the SHMO group tended to be higher than the other groups and Bacteroidaceae in the CEMO and CERB groups were significantly higher than that in the SHMO group. The results demonstrate that the mixture of organisms was fermented with the cecal contents and that the metabolites such as short-chain fatty acid lowered the serum total cholesterol and liver cholesterol concentrations in the rats fed a cholesterol-containing diet.