Cholesteryl ester transfer protein gene polymorphism is a determinant of HDL cholesterol and of the lipoprotein response to a lipid-lowering diet in type 1 diabetes

The TaqIB cholesteryl ester transfer protein (CETP) gene polymorphism (B1B2) is a determinant of HDL cholesterol in nondiabetic populations. Remarkably, this gene effect appears to be modified by environmental factors. We evaluated the effect of this polymorphism on HDL cholesterol levels and on the lipoprotein response to a linoleic acid-enriched, low-cholesterol diet in patients with type 1 diabetes. In 44 consecutive type 1 diabetic patients (35 men), CETP polymorphism, apolipoprotein (apo) E genotype, serum lipoproteins, serum CETP activity (measured with an exogenous substrate assay, n = 30), clinical variables, and a diet history were documented. The 1-year response to diet was assessed in 14 type 1 diabetic patients, including 6 B1B1 and 6 B1B2 individuals. HDL cholesterol was higher in 10 B2B2 than in 14 B1B1 homozygotes (1.63 +/- 0.38 vs. 1.24 +/- 0.23 mmol/l, P < 0.01). HDL cholesterol, adjusted for triglycerides and smoking, was 0.19 mmol/l higher for each B2 allele present. CETP activity levels were not significantly different between CETP genotypes. Multiple regression analysis showed that VLDL + LDL cholesterol was associated with dietary polyunsaturated:saturated fatty acids ratio (P < 0.02) and total fat intake (P < 0.05) in the B1B1 homozygotes only and tended to be related to the presence of the apo E4 allele (P < 0.10). In response to diet, VLDL + LDL cholesterol fell (P < 0.05) and HDL cholesterol remained unchanged in 6 B1B1 homozygotes. In contrast, VLDL + LDL cholesterol was unaltered and HDL cholesterol decreased (P < 0.05) in 6 B1B2 heterozygotes (P < 0.05 for difference in change in VLDL + LDL/HDL cholesterol ratio). This difference in response was unrelated to the apo E genotype. Thus, the TaqIB CETP gene polymorphism is a strong determinant of HDL cholesterol in type 1 diabetes. This gene effect is unlikely to be explained by a major influence on the serum level of CETP activity, as an indirect measure of CETP mass. Our preliminary data suggest that this polymorphism may be a marker of the lipoprotein response to dietary intervention.     

The effect of a low-fat, high-carbohydrate diet on serum high density lipoprotein cholesterol and triglyceride

OBJECTIVE: To determine whether substituting carbohydrate for saturated fat has any adverse effects on serum high density lipoprotein (HDL) cholesterol and triglycerides in free-living individuals. DESIGN: Randomised crossover trial. SETTING: General community. SUBJECTS: Volunteer sample of 38 healthy free-living men with mean (s.d.) age 37 (7) y, moderately elevated serum total cholesterol 5.51 (0.93) mmol/l and body mass index 26.0 (3.6) kg/m2. INTERVENTIONS: Participants completed two six week experimental periods during which they consumed either a traditional Western diet (36%, 18%, and 43% energy from total, saturated, and carbohydrate, respectively) or a low-saturated fat high-carbohydrate diet (22%, 6% and 59% energy from total, saturated, and carbohydrate, respectively). Dietary principles were reinforced regularly, but food choices were self-selected during each experimental period. MAIN OUTCOME MEASURES: Serum lipids, body weight and plasma fatty acids. RESULTS: Reported energy and nutrient intakes, plasma fatty acids, and a drop in weight from 79.1 (12.5) kg on the Western diet to 77.6 (12.0) kg on the high-carbohydrate diet (P < 0.001) confirmed a high level of compliance with experimental diets. Total and low density lipoprotein (LDL) cholesterol fell from 5.52 (1.04) mmol/l and 3.64 (0.88) mmol/l, respectively on the Western diet to 4.76 (1.10) mmol/l and 2.97 (0.94) mmol/l on the high-carbohydrate diet (P < 0.001). HDL cholesterol fell from 1.21 (0.27) mmol/l on the Western diet to 1.07 (0.23) mmol/l on the high-carbohydrate diet (P = 0.057), but the LDL:HDL cholesterol ratio improved from 3.17 (1.05) on the Western diet to 2.88 (0.97) on the high-carbohydrate diet (P = 0.004). Fasting triglyceride levels were unchanged throughout the study. CONCLUSIONS: Replacement of saturated fat with carbohydrate from grains, vegetables, legumes, and fruit reduces total and LDL cholesterol with only a minor effect on HDL cholesterol and triglyceride. It seems that when free living individuals change to a fibre rich high-carbohydrate diet appropriate food choices lead to a modest weight reduction. This may explain why the marked elevation of triglyceride and reduction of HDL cholesterol observed on strictly controlled high-carbohydrate diets may not occur when such diets are followed in practice.     

Cloning and functional expression of a human liver organic cation transporter

OBJECTIVE: The triglyceride-lowering effects of omega-3 fats and HDL cholesterol-raising effects of exercise may be appropriate management for dyslipidemia in NIDDM. However, fish oil may impair glycemic control in NIDDM. The present study examined the effects of moderate aerobic exercise and the incorporation of fish into a low-fat (30% total energy) diet on serum lipids and glycemic control in dyslipidemic NIDDM patients. RESEARCH DESIGN AND METHODS: In a controlled, 8-week intervention, 55 sedentary NIDDM subjects with serum triglycerides > 1.8 mmol/l and/or HDL cholesterol < 1.0 mmol/l were randomly assigned to a low-fat diet (30% daily energy intake) with or without one fish meal daily (3.6 g omega-3/day) and further randomized to a moderate (55-65% VO2max) or light (heart rate < 100 bpm) exercise program. An oral glucose tolerance test (75 g), fasting serum glucose, insulin, lipids, and GHb were measured before and after intervention. Self-monitoring of blood glucose was performed throughout. RESULTS: In the 49 subjects who completed the study, moderate exercise improved aerobic fitness (VO2max) by 12% (from 1.87 to 2.07 l/min, P = 0.0001). Fish consumption reduced triglycerides (0.80 mmol/l, P = 0.03) and HDL3 cholesterol (0.05 mmol/l, P = 0.02) and increased HDL2 cholesterol (0.06 mmol/l, P = 0.01). After adjustment for age, sex, and changes in body weight, fish diets were associated with increases in GHb (0.50%, P = 0.05) and self-monitored glucose (0.57 mmol/l, P = 0.0002), which were prevented by moderate exercise. CONCLUSIONS: A reduced fat diet incorporating one daily fish meal reduces serum triglycerides and increases HDL2 cholesterol in dyslipidemic NIDDM patients. Associated deterioration in glycemic control can be prevented by a concomitant program of moderate exercise.     

Helium-oxygen improves Clinical Asthma Scores in children with acute bronchiolitis

Sprague-Dawley rats (n = 32) were fed diets without fiber (control) or containing 1 or 5% chicory extract or 5% inulin for 4 wk; 0.2% cholesterol was added to all diets. Rats fed chicory extract and inulin diets had significantly higher serum high density lipoprotein (HDL) cholesterol and generally lower low density lipoprotein (LDL) cholesterol concentrations, thus significantly greater ratios of HDL/LDL cholesterol compared with the controls (P < 0.05). The serum apolipoprotein B/apolipoprotein A-1 ratio was significantly lower in rats fed diets containing chicory extract or inulin than that in rats fed fiber-free diets, due to significant reductions in apolipoprotein B concentration (P < 0.05). Greater liver lipid and triglyceride concentrations were observed in rats fed chicory extract or inulin diets compared with the controls (P < 0.05). However, liver phospholipid and cholesterol concentrations were not significantly different among groups (P > 0.05). Addition of 5% inulin to the diet resulted in greater cecal weight, whereas both 5% chicory extract and 5% inulin resulted in greater cecal propionic acid concentration compared with the controls (P < 0.05). Rats fed chicory extract and inulin had significantly greater fecal lipid, cholesterol and bile acid excretions than those fed fiber-free diets (P < 0.05). The results of this study suggest that the improved lipid metabolism observed in rats fed chicory extract (mainly inulin component) may be caused by an alteration in the absorption and/or synthesis of cholesterol, which might result from the changes in cecal fermentation, and by an increase in the fecal excretion of lipid, cholesterol and bile acid.     

Long term metabolic effects of two dietary methods of treating hyperlipidaemia

OBJECTIVES: To compare the long term metabolic effects of two diets for treating hyperlipidaemia. DESIGN: Randomised controlled study: after three weeks of normal (control) diet, subjects were randomly allocated to one of two test diets and followed up for six months. SETTING: Lipid clinic of tertiary referral centre in Naples. SUBJECTS: 63 subjects with primary type IIa and IIb hyperlipoproteinaemia entered the study, and 44 completed it. Exclusion criteria were taking drugs known to influence lipid metabolism, evidence of cardiovascular disease, homozygous familial hypercholesterolaemia, and body mass index over 30. INTERVENTIONS: Two test diets with reduced saturated fat (8%) and cholesterol (approximately 200 mg/day): one was also low in total fat and rich in carbohydrate and fibre, and the other was low in carbohydrate and fibre and rich in polyunsaturated and monounsaturated fats. MAIN OUTCOME MEASURES: Fasting plasma lipid and lipoprotein concentrations; blood glucose, insulin, and triglyceride concentrations before and after a test meal. RESULTS: In comparison with the control diet, both test diets induced significant and similar decreases in low density lipoprotein cholesterol concentrations (by a mean of 0.72 (SE 0.15) mmol/l, P < 0.001, for low total fat diet; by 0.49 (0.18) mmol/l, P < 0.05, for high unsaturated fat diet) and plasma triglyceride concentrations (by 0.21 (0.09) mmol/l, P < 0.05, for low total fat diet; by 0.39 (0.15) mmol/l, P < 0.05, for high unsaturated fat diet), while high density lipoprotein cholesterol concentrations after fasting and plasma glucose and insulin concentrations during test meals were not modified by either diet. CONCLUSIONS: Both test diets are suitable (alone or in combination) for treatment of hypercholesterolaemia.     

Lipid, apoprotein and fibrinogen levels in the blood of male patients following myocardial infarct and the effect of diet on these parameters in ischemic heart disease

The authors have found significantly higher the levels of two not routinely examined risk factors, fibrinogen and lipoprotein (a) in 28 male patients after myocardial infarction than the corresponding data of the PROCAM-study and in the case of fibrinogen than in 23 healthy blood donors. A positive correlation was observed between the LDL-cholesterol and total cholesterol, the LDL-cholesterol and the main apoprotein of LDL, the Apo B level, and between the HDL-cholesterol and the main apoprotein of HDL, the Apo AI. During a 3 week long treatment in the Cardiac Rehabilitation Department the effect of low cholesterol, high unsaturated fatty acid content diet on the lipid, apolipoprotein and fibrinogen levels of male patients suffering from coronary heart disease with cholesterol level higher than 5.2 mmol/l was studied. Significantly decreased the total cholesterol (from 6.21 +/- 0.96 mmol/l to 5.87 +/- 0.98 mmol/l, -5.5%), the LDL-cholesterol (from 3.87 +/- 1.02 mmol/l to 3.61 +/- 0.96 mmol/l, -6.7%), the HDL-cholesterol (from 1.16 +/- 0.39 mmol/l to 1.04 +/- 0.28 mmol/l, -10.3%), the main apoprotein of HDL, the Apo AI (from 1.47 +/- 0.23 g/l to 1.33 +/- 0.29 g/l, -9.5%) and the main apoprotein of LDL, the Apo B level (from 1.59 +/- 0.43 g/l to 1.46 +/- 0.50 g/l, -8.1%). The change of fibrinogen lipoprotein (a) level was not significant. According to the earlier observation of the authors and the data of the literature, the effect of low cholesterol diet on the change of HDL cholesterol was not favourable. The investigation of apolipoprotein levels failed to get closer to the understanding of its mechanism.     

Adenovirus mediated overexpression of human phospholipid transfer protein alters plasma HDL levels in mice

To study the function of plasma phospholipid transfer protein (PLTP) in vivo, a liver directed adenoviral gene transfer system was used to overexpress human PLTP in mice. For the experiments, two strains of mice, wild type (C57/B1) and mice transgenic for the human apoA-I gene (HuApoA-ITg), were utilized. Five days after injection of the recombinant PLTP adenovirus, wild type mice showed a 4-fold increase in serum PLTP activity in (12.2+/-1.3 micromol/ml per h to 48.1+/-8.6 micromol/ml per h (+394%), P < 0.001). The PLTP overexpression induced significant reduction of serum cholesterol (2.46+/-0.08 to 0.69+/-0.42 mmol/l (-72%), P < 0.001), phospholipids (3.10+/-0.06 to 0.90+/-0.24 mmol/l (-71%), P < 0.01), and triglycerides (0.2+/-0.07 to 0.08+/-0.03 mmol/l (-69%), (P < 0.001). ApoA-I was hardly detectable in the serum. These lipid changes were due to a dramatic reduction of high density lipoprotein (HDL). The HuApoA-ITg mice displayed higher basal HDL level and PLTP activity. Adenovirus mediated PLTP overexpression in these mice resulted in a similar decrease of the lipid levels as that seen in the C57/B1 mice. However, the lipoprotein profile revealed a redistribution of HDL, with the appearance of larger buoyant HDL species. The results demonstrate that plasma phospholipid transfer protein in vivo causes high density lipoprotein (HDL) conversion and thereby plays a central role in HDL metabolism.     

Hyperinsulinemia and insulin resistance are associated with multiple abnormalities of lipoprotein subclasses in glucose-tolerant relatives of NIDDM patients. Botnia Study Group

We studied the subclasses of plasma lipoproteins in normolipidemic, glucose-tolerant male relatives of noninsulin dependent diabetic patients (NIDDM), who represented either the lowest (n = 14) or the highest (n = 18) quintiles of fasting plasma insulin. The higher plasma triglyceride level in the high insulin group (1.61 mmol/l vs. 0.87 mmol/l, P < 0.001) was due to multiple differences in triglyceride-rich lipoproteins. The concentrations of larger VLDL1, smaller VLDL2 particles, and IDL particles were 3.8-fold, 2.5-fold, and 1.5-fold higher, respectively, in the high insulin group than in the low insulin group (P < 0.01 or less). In addition, hyperinsulinemic subjects had VLDL1, VLDL2, and IDL particles enriched in lipids and poor in protein. The lower plasma HDL cholesterol level in the high insulin group (1.20 mmol/l vs. 1.44 mmol/l, P < 0.01) compared to the low insulin group was a consequence of a 27% reduction of HDL2a concentration (P < 0.05) and a significantly reduced percentage of cholesterol in HDL3a, HDL3b, and HDL3c subclasses. On the other hand, the percentages of triglycerides in HDL2b, HDL2a, HDL3a, and HDL3b subclasses were 76%, 79%, 61%, and 50% higher, respectively, in the high insulin group than in the low insulin group (P < 0.01 or less). In the combined group, the concentration of VLDL1 and VLDL2 correlated positively with the concentrations of LDL2 and LDL3 and negatively with HDL2b and HDL2a subclasses (P < 0.05 or less). In conclusion, normolipidemic, glucose-tolerant but hyperinsulinemic relatives of NIDDM patients have qualitatively similar lipoprotein abnormalities as NIDDM patients. These abnormalities are not observed in insulin-sensitive relatives, suggesting that they develop in concert with insulin resistance.     

Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia

We have investigated the effects of two fibric acid derivatives, bezafibrate mono (400 mg daily) and gemfibrozil (600 mg b.d.), in 29 patients with type IIb hyperlipoproteinaemia. All patients received placebo and each drug for 8 weeks in randomised order in a double-blind, cross-over study designed to evaluate any different effects of the drugs on serum lipoproteins, cholesteryl ester transfer protein (CETP), cholesteryl ester transfer activity (CETA), plasma fibrinogen, plasminogen activator inhibitor-I (PAI-1) or paraoxonase. Serum cholesterol decreased (P < 0.05) with gemfibrozil, but the effect of bezafibrate on serum cholesterol did not achieve statistical significance (placebo 8.34 +/- 1.05 (mean +/- S.D.), gemfibrozil 7.70 +/- 1.23 and bezafibrate 7.8 +/- 1.37 mmol/l). Both drugs decreased the serum triglyceride concentration (both P < 0.001) (placebo 4.39 (3.13-5.75) (median (interquartile range)), bezafibrate 2.26 (1.89-3.89) and gemfibrozil 2.00 (1.30-3.30) mmol/l) and very low density lipoprotein (VLDL) cholesterol (both P < 0.001) (placebo 1.18 (0.74-2.30), bezafibrate 0.59 (0.34-0.85) and gemfibrozil 0.48 (0.34-0.68) mmol/l). Discontinuous gradient ultracentrifugation (DGU) revealed that Sf 60-400 (large VLDL) decreased by more than 50% and Sf 20-60 (small VLDL) by more than 30% with each of the drugs (both P < 0.001), neither of which affected the composition of these lipoproteins. Gemfibrozil decreased the concentration of Sf 12-20 lipoprotein (intermediate density lipoprotein; IDL) by 23% (P < 0.01), whereas the effect of bezafibrate on this lipoprotein did not achieve statistical significance. Neither drug altered the concentration of apolipoprotein B or of total Sf 0-12 lipoproteins (low density lipoprotein, (LDL)). Both, however, significantly increased the quantity of free cholesterol in Sf 0-12 lipoproteins (P < 0.05). Overall the concentration of triglycerides decreased significantly in all lipoproteins isolated by DGU (Sf 0-12, Sf 12-20, Sf 20-60, Sf 60-400) on gemfibrozil treatment, but only in Sf 20-60 and Sf 60-400 on bezafibrate (all P < 0.05). Both drugs also increased serum high density lipoprotein (HDL) cholesterol (placebo 1.15 +/- 0.29, bezafibrate 1.27 +/- 0.38 (P < 0.01) and gemfibrozil 1.26 +/- 0.49 (P < 0.05) mmol/l) and HDL3 cholesterol concentration (placebo 0.59 +/- 0.12, bezafibrate 0.72 +/- 0.23 (P < 0.001) and gemfibrozil 0.70 +/- 0.24 (P < 0.01) mmol/l). Serum apolipoprotein A1 (apo A1) was increased (P < 0.05) by bezafibrate compared to gemfibrozil (placebo 103 +/- 26, bezafibrate 111 +/- 28 and gemfibrozil 102 +/- 25 mg/dl) and CETA from HDL to VLDL and LDL was decreased (P < 0.05) by bezafibrate compared to placebo, but the apparent decrease with gemfibrozil did not achieve statistical significance (placebo 39.6 +/- 17.7, bezafibrate 32.3 +/- 14.7 and gemfibrozil 33.8 +/- 15.0 nmol/ml/h). Neither drug affected the circulating concentration of CETP. Plasma fibrinogen was increased (P < 0.05) by gemfibrozil (placebo 4.16 (3.38-4.71) and gemfibrozil 4.65 (4.05-5.77) g/l) and was significantly lower (P < 0.001) on bezafibrate (3.60 (3.18-4.54) g/l) than on gemfibrozil treatment. There was a significant (P < 0.05) increase in PAI-1 activity with bezafibrate and a similar trend with gemfibrozil (placebo 41.2 (25.6-64.5), bezafibrate 50.5 (35.1-73.9) and gemfibrozil 48.5 (31.5-5.4 U/l). Neither fibrate influenced plasma concentrations of PAI-1 nor were the activities of lecithin:cholesterol acyl transferase or paraoxonase affected. The major difference in the action of the two drugs on lipoprotein metabolism was the greater effect of gemfibrozil in decreasing the overall serum concentration of Sf 12-20 lipoproteins and the triglycerides in Sf 12-20 and 0-12 lipoproteins. Bezafibrate, however, increased serum apo A1 concentration and significantly decreased CETA. The two drugs also had different effects on the plasma fibrinogen levels, which increased with gemfibrozil and tended to decrea     

Synaptic proteins of the temporal associative area of the neocortex of cats (field Ep) with normal and reduced cognitive capacities

Genetically hypercholesterolaemic RICO rats (male, 6 weeks old) were randomly distributed into 6 experimental groups. The zero-time basal group A was sacrificed at the start of the experiment while the other groups were fed for 6 weeks and then sacrificed. Group B was fed a stock diet. Control group C was fed a high-sucrose (45%) diet with 0.5% added cholesterol. In the diet of group D, only the magnesium (Mg) content was reduced from the level of group C (883 ppm) to 200 ppm. The diet of group E was the same as that of group D with the addition of 12 ppm of fluoride (F) and the diet of group G was the same as that of group E, but with its Mg content elevated from 200 ppm to 300 ppm. Analysis of aortic blood samples, taken before sacrifice, indicated significant increases in total serum cholesterol (p < 0.01), very low density lipoprotein (VLDL) (p < 0.001) and low density lipoprotein (LDL), (p < 0.001) cholesterol, and a trend to lower high density lipoprotein (HDL) cholesterol in group C, as compared to group B. Significantly lower total (p < 0.05), VLDL (p < 0.01) and LDL (p < 0.01) triglycerides were observed in group C when compared to group B. The LDL phospholipids were significantly higher in group C (p < 0.001) than in group B. When cholesterol levels in groups D, E and G were compared with group C, the VLDL cholesterol in group E and the LDL cholesterol in group G were slightly but significantly (p < 0.05) reduced, while total cholesterol and the other subfractions were unaltered. The LDL triglycerides of groups E and G were significantly smaller still than the already small fraction in group C. The VLDL triglyceride in group E was significantly lower than that of group C (35% reduction, p < 0.001), D and G (p < 0.05). Phospholipids were slightly but significantly reduced in the VLDL fraction of group E and in the LDL fraction of group G (p < 0.05 and 0.01, respectively), as compared to those of group C.     

Comparative studies on the substrate specificity of lecithin:cholesterol acyltransferase towards the molecular species of phosphatidylcholine in the plasma of 14 vertebrates

We have studied, in a prospective blinded fashion, the effects of regular and extended-release gemfibrozil on plasma lipoprotein and apolipoprotein (apo) levels in hypercholesterolemic subjects with decreased high density lipoprotein (HDL) cholesterol (C) levels. Study participants were men and women 19 to 80 years of age with baseline plasma low density lipoprotein (LDL) C levels > or = 4.5 mmol/l (175 mg/dl), HDL-C levels < or = 1.2 mmol/l (45 mg/dl), and triglyceride levels < or = 3.4 mmol/L (300 mg/dl). All subjects were stabilized on a diet for eight weeks prior to entry into two different protocols. In the first protocol 229 subjects were randomized to placebo or extended-release gemfibrozil (1200 mg/day) for 3 months (placebo trial). In the second protocol 655 subjects were randomized to regular or extended-release gemfibrozil (1200 mg/day) for 6 months (equivalency trial). Changes in lipids and apos were stratified by baseline HDL-C levels (< 0.9 mmol/l, and 0.9-12.2 mmol/l). In both studies, treatment with gemfibrozil, either regular or extended-release, was associated with significant (P < 0.05) decreases in plasma very low density lipoprotein (VLDL) C and triglyceride levels of 42-45% and 33-37%, respectively, in subjects with HDL-C level < 0.9 mmol/l, and of 38-47% and 32-39%, respectively, in patients with HDL-C levels of 0.9-1.2 mmol/l. Modest reductions from baseline in directly measured LDL-C levels were observed in both groups (3-6% and 8-9%, respectively). These reductions were less than those observed for calculated LDL-C (7-10% and 11%, respectively). For apo B, reductions were 11-14% and 16-17% in the two groups. HDL-C, apo A-I, and apo A-II levels increased by 15-16%, 5-6%, and 21-25%, respectively, in patients with HDL-C < 0.9 mmol/l, and by 6-7%, 2-3%, and 19-22%, respectively, in patients with HDL-C of 0.9-1.2 mmol/l. These differences in HDL-C levels reached statistical significance in the equivalency trial (P < 0.0001) and were independent of baseline triglyceride levels. Our data indicate that gemfibrozil, either regular or extended-release, is highly effective in lowering plasma triglyceride levels and increases HDL-C levels by approximately 15% in hypercholesterolemic patients with low HDL-C levels (< 0.9 mmol/l). Moreover, this agent lowers VLDL-C somewhat more than triglyceride, resulting in an underestimation of calculated VLDL-C reductions and in an overestimation of calculated LDL-C reductions. This agent also raises apo A-II levels much more than apo A-I levels.     

Dietary stearic acid reduces plasma and hepatic cholesterol concentrations without increasing bile acid excretion in cholesterol-fed hamsters

Although there is general agreement that saturated fatty acids elevate plasma cholesterol concentrations, the relative effects of individual fatty acids on cholesterol and bile acid metabolism are less clear. In this study, cholesterol and bile acid responses to diets enriched in different saturated fatty acids were investigated in hamsters. The six diets examined were as follows: 5% fat (g/100 g) enriched in palmitic acid (16:0) with no cholesterol, 5% fat 16:0-enriched, 0.05% cholesterol (wt/wt), and four diets containing 0.05% cholesterol and 15% fat with each diet enriched in lauric (12:0), myristic (14:0), palmitic (16:0), or stearic acid (18:0). Total plasma cholesterol concentration was significantly greater in hamsters fed the 14:0-enriched diet relative to those fed the 18:0-enriched diet (P < 0.05). Both plasma and liver cholesterol concentrations of hamsters fed 18:0 did not differ from those of the group fed no dietary cholesterol. In all instances, differences in total plasma cholesterol were accounted for within the HDL fraction; no significant treatment differences in VLDL or LDL cholesterol were found. Total daily fecal bile acid excretion was higher in hamsters fed the 15% fat 16:0 diet compared with those fed no dietary cholesterol (P < 0.05), but not significantly different from other treatment groups. There was greater deoxycholic acid excretion (P < 0.05) from hamsters fed the 14:0 and 16:0 diets compared with those fed the 18:0-enriched diet. Small intestinal + gallbladder bile acids, an index of pool size, did not differ significantly among the groups. The observed relative hypocholesterolemic effect of stearic acid was not mediated by increased bile acid excretion.     

Effect of dietary fats rich in lauric, myristic, palmitic, oleic or linoleic acid on plasma, hepatic and biliary lipids in cholesterol-fed hamsters

Effects of different dietary fats on plasma, hepatic and biliary lipids were determined in male golden Syrian hamsters (Mesocricetus auratus) fed on purified diets for 7 weeks. Diets were made by blending different fats containing characteristic fatty acids: butter (14:0 + 16:0), palm stearin (16:0), coconut oil (12:0 + 14:0), rapeseed oil (18:1), olive oil (18:1) and sunflowerseed oil (18:2). In all diets except the sunflowerseed oil diet dietary 18:2 was held constant at 2% energy. Total fat supplied 12% of energy and cholesterol was added at 4 g/kg diet. Plasma cholesterol and triacyglycerol concentrations were increased by dietary cholesterol. After 7 weeks, plasma cholesterol concentrations were highest with the palm stearin, coconut oil and olive oil diets (8.9, 8.9 and 9.2 mmol/l) and lowest with the rapeseed oil and sunflowerseed oil diets (6.7 and 5.5 mmol/l) while the butter diet was intermediate (8.5 mmol/l). Hepatic cholesterol concentration was highest in hamsters fed on the olive oil diet and lowest with the palm stearin diet (228 v. 144 mumol/g liver). Biliary lipids, lithogenic index and bile acid profile of the gall-bladder bile did not differ significantly among the six diets. Although the gallstone incidence was generally low in this study, three out of 10 hamsters fed on the palm stearin diet developed cholesterol gallstones. In contrast, no cholesterol gallstones were found with the other diets. Rapeseed and sunflowerseed oils caused the lowest plasma cholesterol and triacyglycerol concentrations whereas olive oil failed to demonstrate a cholesterol-lowering effect compared with diets rich in saturated fatty acids. Since 18:2 was kept constant at 2% of energy in all diets, the different responses to rapeseed and olive oils could possibly be attributed to their different contents of 16:0 (5.6% v. 12.8% respectively). Other possible explanations are discussed.     

Increases in dietary cholesterol and fat raise levels of apoprotein E-containing lipoproteins in the plasma of man

Previous studies from this laboratory have determined that diets containing the usual amounts of fat to which are added 750-1500 mg/day cholesterol elevate the plasma cholesterol concentration by variable amounts, depending upon the ratio of polyunsaturated to saturated fatty acids (P/S ratio) of the diet. Diets with P/S ratios of 0.25-0.4 are accompanied by elevations of low density lipoprotein (LDL) cholesterol, whereas diets with a P/S ratio of 2.5 produce no significant changes in cholesterol levels. On the low P/S ratio diets, the structure, composition, and interaction with cultured fibroblasts of LDL are not significantly changed. Plasma high density lipoprotein (HDL) cholesterol levels remain constant, but HDL2 increase relative to HDL3. In the present study, not only dietary cholesterol but also total dietary fat was altered. Six normal young men were fed a basal diet consisting of 18% protein, 51% carbohydrate, and 30% fat, containing 250 mg/day cholesterol. After 2 weeks, an experimental diet consisting of 18% protein, 42% carbohydrate, and 39% fat, containing 1760 mg/day cholesterol, was fed for 4 weeks. The P/S ratios of both diets were about 0.4. Plasma samples were taken twice during each dietary period from 12- to 14-h-fasted subjects and analyzed for their contents of lipoprotein lipids. Plasma levels of LDL and HDL cholesterol increased by 30 and 13 mg/dl, respectively; total and very low density lipoprotein (VLDL) triglyceride concentrations were unaltered. The plasma concentrations of apoproteins (apo) B, E. and A-I, but not A-II, were elevated. Plasma samples also were studied by zonal ultracentrifugation, gel permeation column chromatography, and Pevikon electrophoresis. Although on zonal ultracentrifugation the total concentrations of LDL were increased, the flotation properties and chemical compositions of LDL were not changed. By contrast, HDL2 and HDL3L concentrations increased, and HDL2 became enriched with cholesteryl esters. On gel permeation chromatography, with the subjects on the basal diet, plasma cholesterol eluted in two peaks, corresponding to LDL and HDL. The sizes of the peaks increased on the experimental diet. ApoE eluted in two peaks: one at the leading edge of LDL (corresponding to VLDL or IDL) and the other in the area between LDL and HDL, corresponding to HDLC. On the experimental diet, the apoE peak between LDL and HDL increased. On Pevikon electrophoresis apoE migrated between the LDL and HDL bands. This apoE peak was increased on the experimental diet. These findings suggest that increasing the concentrations of both dietary cholesterol and total fat can increase the levels of plasma LDL, HDL2, and HDLC in fasting normal subjects. Thus, the concentrations of some putatively atherogenic as well as antiatherogenic lipoproteins increased in plasma, and the apparent paradox between the epidemiological and metabolic behaviors of some lipoproteins remains. Clearly, more work is needed to resolve the roles of various lipoproteins in plasma in atherosclerosis.     

Effects of margarine compared with those of butter on blood lipid profiles related to cardiovascular disease risk factors in normolipemic adults fed controlled diets

Effects of butter and 2 types of margarine on blood lipid and lipoprotein concentrations were compared in a controlled diet study with 23 men and 23 women. Table spreads, added to a common basal diet, provided 8.3% of energy as fat. Diets averaged 34.6% of energy as fat and 15.5% as protein. Each diet was fed for 5 wk in a 3 x 3 Latin-square design. One margarine (TFA-M) approximated the average trans monoene content of trans fatty acid-containing margarines in the United States (17% trans fatty acids by dry wt). The other margarine (PUFA-M) was free of trans unsaturated fatty acids; it contained approximately twice the polyunsaturated fatty acid content of TFA-M (49% compared with 27% polyunsaturated fatty acids). The tub-type margarines had similar physical properties at ambient temperature. Fasting blood lipids and lipoproteins were determined in 2 samples taken from the subjects during the fifth week of each dietary treatment. Compared with butter, total cholesterol was 3.5% lower (P=0.009) after consumption of TFA-M and 5.4% lower (P< 0.001) after consumption of PUFA-M. Similarly, LDL cholesterol was 4.9% lower (P=0.005) and 6.7% lower (P< 0.001) after consumption of TFA-M and PUFA-M, respectively. Neither margarine differed from butter in its effect on HDL cholesterol or triacylglycerols. Thus, consumption of TFA-M or PUFA-M improved blood lipid profiles for the major lipoproteins associated with cardiovascular risk when compared with butter, with a greater improvement with PUFA-M than with TFA-M.     

Impact of gender on the metabolism of apolipoprotein A-I in HDL subclasses LpAI and LpAI:AII in older subjects

The behavior of apolipoprotein (apo) A-I in lipoprotein (Lp) AI and LpAI:AII was studied in 11 postmenopausal females and 11 males matched for plasma triglyceride and total cholesterol levels. Subjects consumed a baseline diet [35% fat (14% saturated, 15% monounsaturated, and 7% polyunsaturated), 15% protein, 49% carbohydrate, and 147 mg cholesterol/1000 kcal] for 6 weeks before the start of the kinetic study. At the end of the diet period, using a primed-constant infusion of [5,5,5-2H3]leucine, residence times (RT) and secretion rates (SR) of apoA-I were determined in 2 subpopulations of high-density lipoprotein (HDL) particles, LpAI and LpAI:AII. Plasma total cholesterol, low-density lipoprotein cholesterol, and triglyceride concentrations were similar in males and females. The mean plasma HDL cholesterol concentration in males (1.14 +/- 0.23 mmol/L; mean +/- SD) was lower than in females (1.42 +/- 0.18 mmol/L; P =. 0034). Similarly, the mean plasma concentration of apoA-I in males (130 +/- 21 mg/dL) was lower than that in females (150 +/- 19 mg/dL; P = .0421). The RT of apoA-I in either LpAI or LpAI:AII was similar between men and women. Despite the higher plasma apo A-I levels in female compared with male subjects, total apoA-I and apoA-I in LpAI and LpAI:AII pool sizes were similar between the two groups, attributable to the lower body weight of the female subjects. The mean SR of total apoA-I in males (8.5 +/- 2.7 mg.kg-1.d-1) was 22% lower than in females (10.9 +/- 2.3 mg.kg-1.d-1; P = .0389). The SR of both apoA-I in LpAI and LpAI:AII was lower in males than females, although the differences did not reach statistical significance. These data suggest that the difference observed in HDL cholesterol concentration between males and females is attributable to SR of apoA-I and not the catabolic rate.     

Plasma lipoprotein distribution of apoC-III in normolipidemic and hypertriglyceridemic subjects: comparison of the apoC-III to apoE ratio in different lipoprotein fractions

In order to assess the relationship between plasma accumulation of triglyceride-rich lipoproteins (TRL) and lipoprotein levels of apoC-III and apoE, we have measured apoC-III and apoE in lipoproteins separated according to size (by automated gel filtration chromatography) from plasma of normolipidemic subjects (plasma triglyceride (TG): 0.84 +/- 0.10 mmol/l; mean +/- SE, n = 8), and from type III (n = 8) and type IV (n = 8) hyperlipoproteinemic patients, matched for plasma TG (5.76 +/- 0.62 v 5.55 +/- 0.45 mmol/l, resp.). Total plasma apoC-III concentration was similar in type III and type IV patients (33.1 +/- 3.4 v 37.6 +/- 4.4 mg/dl, respectively), but was significantly increased compared to normolipidemic controls (10.0 +/- 1.0 mg/dl, P < 0.001). TRL apoC-III was lower and high density lipoprotein (HDL) apoC-III was significantly higher in type III versus type IV subjects (14.8 +/- 3.2 vs. 22.8 +/- 3.0 mg/dl, P < 0.05; 8.3 +/- 1.0 vs. 5.2 +/- 0.5 mg/dl, P < 0.05). Plasma concentration of apoC-III in lipoproteins that eluted between TRL and HDL (intermediate-sized lipoproteins, ISL) was similar in the two hypertriglyceridemic groups (10.1 +/- 1.3 vs. 9.7 +/- 1.6 mg/dl), but was significantly higher (P< 0.05) than controls (2.2 +/- 0.3 mg/dl). TRL, ISL, and HDL apoE concentrations were significantly higher in type III versus type IV subjects (P < 0.05). All lipoprotein fractions in type III patients were characterized by lower apoC-III to apoE ratios. In contrast, the TRL apoC-III to apoE ratio of type IV patients was similar and the ISL apoC-III to apoE ratio was significantly higher, compared to normolipidemic individuals. These results indicate that compared to normolipidemic individuals, remnant-like lipoproteins in the ISL fraction of type IV patients are enriched in apoC-III relative to apoE, whereas those of type III patients are enriched in apoE relative to apoC-III.     

Systemic vasculitis: classification and serologic diagnosis

Cardiovascular morbidity and mortality in hemodialyzed patients are increased due to the frequently abnormal lipid metabolism. It has been reported that this abnormal lipid metabolism could be partially corrected by some highly permeable membranes, such as polysulfone or cellulose triacetate. We investigated the influence of 4 months of dialysis with a polyamide membrane upon the course of lipid parameters in 6 patients presenting a hypertriglyceridemia > 2 mmol/l while on bicarbonate dialysis with a cellulose membrane. Lipid parameters improved after 4 months of hemodialysis with a polyamide membrane. Serum triglyceride and cholesterol levels decreased, while HDL cholesterol and HDL levels rose significantly (p < 0.05). Apolipoprotein B decreased significantly (p < 0.05). Following heparin administration, lipoprotein lipase activity improved (p < 0.02), associated with a decrease apolipoprotein C3 (p < 0.05). The fractional clearance rate of triglycerides rose significantly (p < 0.01). The use of highly permeable polyamide membranes results in a significant improvement in lipid disturbances of dialysis patients due to an increased lipoprotein lipase activity, induced perhaps by the removal of circulating inhibitors such as apolipoprotein C3.     

Origins of neural crest cell diversity

The effect of diets containing 50% of fat calories from butter, butter enriched with mono- and polyunsaturated fatty acids, and margarines with and without trans fatty acids on the serum lipids of 38 healthy men in a free-living condition have been determined. Serum lipid responses to the high level of individual dietary fats were unexpectedly small. The butter diet produced a small, but significant rise (5%) in the total serum cholesterol and low density lipoprotein (LDL)-cholesterol, relative to all other diets. Enrichment of butter with either olive oil (50/50) or sunflower oil (50/50) failed to reduce serum lipid levels below habitual diet values. Hard margarine, containing 29% trans fatty acids, caused a decrease in apolipoprotein A-I and B levels, but did not change total serum cholesterol or LDL-cholesterol levels, relative to habitual diet values. A soft margarine, high in linoleate, with no trans fatty acids reduced total cholesterol, LDL-cholesterol, and apolipoprotein B significantly, relative to all diets. Soft margarine high density lipoprotein (HDL)-cholesterol levels remained unchanged, but apolipoprotein A-I values were decreased relative to habitual and butter diets. The quantities of saturated fatty acids and the sum of monounsaturated and polyunsaturated fatty acids consumed on the hard and soft margarines were equal; therefore, the different response of serum cholesterol and LDL-cholesterol between these two diets is attributable to the trans fatty acids in the hard margarine. The data indicate that trans fatty acids are not metabolically equivalent to the natural cis isomers and that they affect the serum lipid profile adversely.     

Dietary fat saturation and chain length modulate guinea pig hepatic cholesterol metabolism

The effects of dietary fat saturation and saturated fatty acid composition on plasma lipoprotein concentrations and hepatic cholesterol metabolism were investigated in guinea pigs. Animals were fed semipurified diets containing 15 g fat/100 g diet, as palm kernel, palm oil, beef tallow, lard, olive oil or corn oil. Plasma lipoprotein concentrations were significantly altered by the type of dietary fat. The LDL cholesterol concentration was highest in animals fed the diet with palm kernel and lowest in animals fed the diet with corn oil, whereas HDL cholesterol was lowest in beef tallow-fed guinea pigs (P < 0.01). Hepatic cholesteryl ester concentrations were 100% higher in animals fed diets containing polyunsaturated corn oil and monounsaturated olive oil compared with animals fed any of the saturated fat diets (P < 0.01). Hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity varied in the different dietary fat groups independent of hepatic cholesterol pools or plasma LDL concentrations. In contrast, hepatic acyl-CoA: cholesterol acyltransferase (ACAT) activity was significantly correlated with plasma LDL cholesterol across all dietary groups (r = 0.63, P < 0.001). These data demonstrate that regulation of hepatic HMG-CoA reductase activity is relatively independent of changes in plasma lipoprotein levels, whereas hepatic ACAT activity exhibits a positive correlation with plasma LDL cholesterol concentrations.