Exclusive breast-feeding and weaning: effect on serum cholesterol and lipoprotein concentrations in infants during the first year of life.The total serum cholesterol concentration of infants was investigated at birth (n = 193) and at the ages of 2 (n = 192), 4 (n = 192), 6 (n = 190), 9 (n = 188), and 12 months (n = 196). Concentrations of cholesterol--very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein-2 (HDL2), HDL3--and apoprotein B were analyzed in 36 infants at 2, 6, 9, and 12 months of age. Serum cholesterol concentration rose significantly more slowly in the weaned infants compared with exclusively breast-fed infants. The mean difference in total serum cholesterol value between the exclusively breast-fed and weaned infants was largest at ages 2 (0.9 mmol/L, P less than .001), 4 (0.6 mmol/L, P less than .01), and 6 months (0.5 mmol/L, P less than .01). The LDL cholesterol concentration was lower in weaned infants compared with exclusively breast-fed infants at age 2 and 6 months; the mean difference in LDL cholesterol value was 0.9 mmol/L at age 2 months (P less than .001) and 0.7 mmol/L at age 6 months (P less than .025). Also, the apoprotein B concentration was lower in weaned infants; the mean difference was 24 mg/dL at age 2 months (P less than .01) and 30 mg/dL at age 6 months (P less than .05). The apoprotein B-LDL cholesterol ratio was stable and similar in both feeding groups through the year. The HDL2 cholesterol concentration was lower in the formula-fed than in breast-fed infants at 2 months of age while the VLDL and HDL3 cholesterol concentrations were independent of the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study.OBJECTIVE--To estimate the influence of plasma total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease. DESIGN--The Copenhagen City Heart Study is a prospective observational survey with two cardiovascular examinations at five year intervals. Non-fasting plasma lipids were measured in participants once at each examination, along with other variables. The Cox regression model was used to establish the effect of the factors recorded on cerebrovascular events of mostly, but not exclusively, ischaemic origin. SUBJECTS--19,698 women and men at least 20 years old, randomly selected after age stratification from an area of central Copenhagen. MAIN OUTCOME MEASURES--Initial cases of stroke and transient ischaemic attack recorded from hospital records and death certificates from 1976 through 1988. RESULTS--660 non-haemorrhagic and 33 haemorrhagic events were recorded. Total cholesterol was positively associated with risk of non-haemorrhagic events, but only for levels > 8 mmol/l, corresponding to the upper 5% of the distribution in the study population. For lower plasma cholesterol values the relative risk remained nearly constant. Plasma triglyceride concentration was significantly, positively associated with risk of non-haemorrhagic events. The relative risk corresponding to an increase of 1 mmol/l was 1.12 (95% confidence interval 1.07 to 1.16). There was a negative, log linear association between high density lipoprotein cholesterol and risk of non-haemorrhagic events (0.53 (0.34 to 0.83)). There was no indication that the effects of plasma lipids were different in women and men. CONCLUSIONS--The pattern of the association between plasma cholesterol and risk of ischaemic cerebrovascular disease was not log linear, and the increased risk was confined to the upper 5% of the cholesterol distribution. Further studies should concentrate on the association between plasma cholesterol and verified haemorrhagic stroke.

Bile acid malabsorption as a cause of hypocholesterolemia seen in patients with chronic pancreatitis.A determination of caloric consumption based on a dietary survey table, fat and cholesterol intake, and analyses of fecal fatty acids and neutral sterols, and bile acid analysis (gas chromatographic method) were conducted on 33 subjects (including 17 patients with chronic pancreatitis and 16 normal controls). The factors related to hypocholesterolemia in chronic pancreatitis (CP) patients were investigated and the following conclusions were obtained: (1) The total caloric intake and fat consumption by the CP patients were significantly lower with the exception of cholesterol consumption. (2) Significant increases were noted in fecal fat, neutral sterols, and bile acid excretion by the CP patients. (3) A significant positive correlation was noted between the total cholesterol and body mass index (BMI), reaffirming that the cholesterol level can be used as an indicator of nutritional status. (4) A significant negative correlation was noted between the serum total cholesterol and fecal bile acid excretion. These findings indicate that CP patients suffer from neutral sterol malabsorption, in addition to dietary fat maldigestion and bile acid malabsorption. Furthermore, bile acid malabsorption is cited as a factor in the development of hypocholesterolemia in CP patients.

Endothelial nitric oxide synthase activity in aorta of normocholesterolemic rabbits: regional variation and the effect of estrogen.OBJECTIVE: Several animal studies suggest that nitric oxide (NO) produced by the endothelium attenuates arterial cholesterol accumulation. In the present study we have asked the following questions: (1) is the regional variation in aortic cholesterol accumulation in hypercholesterolemic rabbits preceded by a regional variation in endothelial NO synthase (eNOS) activity in normocholesterolemic rabbits, and (2) is the antiatherogenic effect of estrogen in hypercholesterolemic rabbits preceded by a higher eNOS activity in normocholesterolemic rabbits. METHODS: The eNOS activity was determined by conversion of 14C-L-arginine to 14C-L-citrulline in freshly isolated endothelial cells of aorta in normocholesterolemic rabbits. In the regional variation study, 16 male and eight female rabbits were used. In the estrogen study, ovariectomized female rabbits were subcutaneously injected three times weekly with either 17beta-estradiol (n=7) or vehicle (n=7) for 18 weeks. RESULTS: In the regional variation study, the atherosclerosis prone aortic arch showed a significant lower eNOS activity than the more resistant abdominal aorta in both male (P<0.0001) and female (P<0.05) rabbits. In the estrogen study, the eNOS activity in the aortic arch and upper thoracic aorta was significantly higher in the estrogen than in the vehicle rabbits (P<0.05). In the lower thoracic aorta, however, the eNOS activity was the same. CONCLUSION: The findings suggest that a high NO production in the luminal endothelium of the arterial wall precedes a low cholesterol accumulation during a subsequent period of hypercholesterolemia.

A linoleic acid enriched diet increases serum cholesterol esterification by lecithin:cholesterol acyltransferase in meal-fed rats.Dietary fats are known to influence the fatty acid profile of plasma lipids, including phospholipids which are substrates of lecithin:cholesterol acyltransferase (LCAT; EC 2.3.1.43), an important enzyme in lipoprotein metabolism. We tested whether the dietary fatty acid profile has an effect on LCAT activity in an animal model. Rats were conditioned to eat two meals per day, which were enriched in either palmitic, oleic or linoleic acids, for 10 weeks. Serum was isolated from blood samples taken prior to the meal. The LCAT activity was determined in two ways: (1) by measuring serum cholesterol esterification rates, which are an estimate of LCAT action on endogenous lipoproteins, and (2) by measuring serum LCAT activity levels with excess exogenous substrates, an estimate of LCAT mass. Animals receiving the linoleic acid diet had lower serum concentrations of unesterified cholesterol and triglycerides, if compared with animals fed oleic acid or palmitic acid diets (p < 0.05). Serum LCAT activity levels (measured with excess exogenous substrates) were not different, but both the absolute and fractional rates of cholesterol esterification were highest on the linoleic acid rich diet (p < 0.01), showing that LCAT action on endogenous lipoproteins is improved. No differences were found in serum apolipoprotein B and A-IV concentrations between the dietary groups. Apolipoprotein A-I levels were lowest in the palmitic acid group (oleic and linoleic > palmitic; p < 0.05), and apolipoprotein E levels were highest in the palmitic acid group (palmitic > oleic and linoleic; p < 0.05). It is concluded that a linoleic acid rich diet may cause increased metabolism of serum cholesterol by LCAT in rats. This effect is not due to elevated serum concentrations of LCAT or of its apolipoprotein activators, but most likely to changes in the chemical composition of endogenous lipoprotein substrates. It remains to be established whether the serum cholesterol esterification rates measured in vitro are related to in vivo rates of reverse cholesterol transport.

RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase.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-azabicyclo[2-2-2]octane 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 [14C]cholesterol biosynthesis from [14C]mevalonate in the liver with an ED50 value of 5 mg/kg. Diacid metabolites of [14C]farnesyl 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.

Additive hypocholesterolemic effect of psyllium and cholestyramine in the hamster: influence on fecal sterol and bile acid profiles.Recent findings suggest that the effects of cholestyramine and psyllium in combination could be additive for cholesterol-lowering. We therefore examined the effect of both agents, alone and in combination, on lipoprotein cholesterol and neutral and acidic steroid excretion in the hamster. Animals (n = 8/group) were fed for 21 days, either a basal chow diet supplemented with 10% palm oil and 0.2% cholesterol, or one of four treatments consisting of the basal diet plus: 5.5% cellulose; 5% psyllium with 0.5% cellulose; 0.5% cholestyramine with 5% cellulose; or 5% psyllium with 0.5% cholestyramine. Psyllium and cholestyramine both had significant hypocholesterolemic effects, but in combination produced additive reductions in lipoprotein and hepatic cholesterol. Psyllium, cholestyramine, and the combination increased total bile acid excretion by 26%, 57%, and 79%, respectively. Psyllium affected only unconjugated bile acid excretion while cholestyramine also increased the excretion of conjugated and primary bile acids. Neither agent, nor the combination, affected fecal neutral sterol excretion. We conclude that, while both agents lower cholesterol by a mechanism of increased bile acid excretion, these studies indicate that psyllium does not bind bile acids in vivo and lend further support for the concomitant use of these agents for cholesterol-lowering.

Lipids, lipoproteins and apolipoproteins AI, AII, B, CII, CIII and E in newborns.In this study lipid and apolipoprotein patterns were investigated at birth and compared with those of adults. In cord sera, cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were 38.2, 46.2, 50.5, and 31.9%, respectively, of adult values. Apolipoprotein AII, B and CIII were 48.6, 30.6 and 44.5% of adult values, while apo AI, apo CII and apo E showed values approaching those of adults (63.4, 73.3 and 89.7%, respectively). Also cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios were lower in newborns. In cord sera, lipids were correlated with various apolipoproteins in a surprisingly different way from adult sera. HDL cholesterol was not inversely correlated with triglycerides, and showed a highly positive correlation with apo E, apo CII and apo CIII, which did not correlate with HDL cholesterol in adults. These data supported the presence of significant differences in plasma concentrations and composition of lipoproteins at birth. Therefore HDL, apo CII, and apo E seem to play a different and more important metabolic role in neonatal lipid metabolism.

Variation in the low density lipoprotein receptor gene is associated with differences in plasma low density lipoprotein cholesterol levels in young and old normal individuals from Italy.We have used four restriction fragment length polymorphisms (RFLPs) of the human low density lipoprotein receptor (LDL-R) gene, detected by the restriction enzymes Ava II, Pvu II, and ApaLI (5' and 3'), to study the effect of variation at this gene locus in determining plasma cholesterol and LDL cholesterol levels. Two hundred eighty-nine normolipidemic individuals were studied from the Liguria region of Italy. The Pvu II RFLP was significantly associated with differences in plasma total and LDL cholesterol levels, explaining 9.6% of the sample variance in LDL cholesterol levels. The other RFLPs, which are in strong linkage disequilibrium with the Pvu II RFLP, were associated with smaller effects on LDL cholesterol. The Pvu II allele, distinguished by the presence of the variable cutting site (P2 allele), was associated with lower levels of total and LDL cholesterol, and the frequency of the P2 allele was significantly reduced in individuals with LDL cholesterol levels higher than the 75th percentile. The frequency of the P2 allele was significantly higher in the group of individuals over 65 years old, and in this group the P2 allele was also associated with a similar reduction in LDL cholesterol levels. Because of linkage disequilibrium, only four RFLP haplotypes were common in this sample. Of these, only the haplotype P2A2VI (relative frequency, 0.269) was associated with a reduction in LDL cholesterol (average excess, -11.5 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Epidemiology of low cholesterol levels in older adults. The Cardiovascular Health Study.BACKGROUND. Low cholesterol levels have been associated with increased mortality from stroke, cancer, and other noncardiovascular diseases, but the reasons for this association remain unclear. One explanation is that persons with low cholesterol levels have early or occult disease that eventually leads to their deaths. METHODS AND RESULTS. This possibility was explored in 2,091 men and 2,714 women 65-100 years old in the Cardiovascular Health Study, a multicenter observational study of risk factors for heart disease and stroke in older adults. Cholesterol levels < or = 160 mg/dL were present in 11.6% of men and 3.7% of women and increased in prevalence with age. After adjustment for age, total cholesterol levels in this range were associated with a twofold increased prevalence of treated diabetes in men and women and with a twofold increased prevalence of cancer diagnosed in the preceding 5 years in women only. Low cholesterol was also associated with lower levels of hemoglobin, albumin, and factor VII, suggesting a link with hepatic synthetic function. On multivariate analysis, factors most strongly associated with low cholesterol levels in men and women were decreased factor VII levels, decreased albumin, and diabetes. CONCLUSIONS. Cross-sectional associations with low cholesterol levels differ by sex and suggest poorer health by some measures. The observed relations with treated diabetes and impaired hepatic synthetic function should be examined for risk of mortality in longitudinal data from this and other observational studies.