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The chemical composition and metabolism of lipoproteins in a population of Benedictine nuns were studied after 5-month periods during which the predominant dietary fats were sunflower oil, peanut oil, palm oil, or milk fats (butter and cream). The population was divided into three groups. The control group (C) included twelve subjects selected at random by taking two subjects per age pool among those with plasma cholesterol less than 230 mg/dl. Groups H1 and H2 were selected at random in the same way, among those with plasma cholesterol greater than 230 mg/dl. Each group comprised six subjects and differed from each other in the amount of plasma cholesteryl esters, i.e., below and above the mean value of group C, for H1 and H2, respectively. Changes in the degree of saturation of the predominant fat of the diet were associated with changes in both the chemical composition of lipoproteins and their cellular metabolism studied in fibroblast cultures. No significant difference between the normocholesterolemic subjects of group C and the ''high risk'' subjects of groups H1 and H2 was found.

This study evaluated the postprandial (PP) response to an oral fat load in 28 male patients with type 2 diabetes (mean HbA1c of 5.1%), all receiving metformin and performing physical exercise, compared with healthy subjects. The effects of micronized fenofibrate (200 mg once daily) on triglycerides (TG) and retinyl palmitate (RP) responses, lipoprotein mass concentrations, post-heparin lipase activities and coagulation factors were investigated after a 16-week double-blind, placebo-controlled period. Higher and delayed TG response after the oral fat load (P<0.001) corresponding to increases in both intestinally and endogenous TG-rich lipoproteins and lower lipoprotein lipase (LPL) activity 30 and 60 min post-heparin injection (P<0.05) were observed in the patients as compared with controls. Fasting PAI-1 activity, 6 h PP Factor VII and PAI-1 activities were higher in patients (P=0.036, P=0.032 and P=0.017, respectively). After fenofibrate treatment, TG and RP responses and peak LPL activity were no more significantly different from controls at baseline. Compared with placebo, fasting TG-rich lipoproteins and HDL(3) mass concentrations were significantly lower and higher, respectively; PP chylomicrons and very low density lipoprotein (VLDL) mass concentrations were lower; fasting and PP fibrinogen levels were significantly reduced after fenofibrate treatment. Diabetes control was unchanged throughout the study. Fenofibrate normalized the abnormal PP response and improved the fasting lipoprotein abnormalities in patients with type 2 diabetes and optimal glucose control.

The effect of an alpha-blocking agent and of a beta-blocking agent on the biosynthesis of extracellular matrix macromolecules of the arterial wall was investigated. Rabbit aorta explants were cultured up to 48 hours with radioactive proline, lysine or glucosamine. In presence of these drugs, at concentration shown to be effective for the inhibition of platelet-endothelial cell interactions (10(-7) M), the incorporation of 14C proline in total macromolecular proline was higher than in macromolecular hydroxyproline suggesting a relatively higher rate of biosynthesis of non-collagenous proteins as compared to collagens. The alpha-blocking increased the incorporation of 14C proline in collagenous and non-collagenous proteins after 18 hours of incubation. beta-blocking also increased the incorporation of proline in macromolecular proline and hydroxyproline as compared to control cultures. Both increased the incorporation of 3H glucosamine in newly synthesised glycosaminoglycans. beta-blocking increased mainly the neosynthesis of heparan sulphate, alpha-blocking that of hyaluronan. The incorporation of 14C-lysine in crosslinked, insoluble elastin was not modified. These experiments confirm that alpha and beta-blocking agents can influence not only the tonus of aortic smooth muscle cells but also the relative rates of biosynthesis of extracellular matrix macromolecules. This effect should be taken in consideration for the evaluation of the long range effect of alpha and beta-blocking drugs on the vascular wall.

Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach. An estimation of the proportions performed with the HOMOG3R program showed that an LDLR gene defect was involved in approximately 50% of the families (P = 0.001). On the other hand, the estimated contribution of an APOB gene defect was only 15%. This low estimation of ADH due to an APOB gene defect is further strengthened by the existence of only two probands carrying the APOB (R3500Q) mutation in the sample. More importantly and surprisingly, 35% of the families in the sample were estimated to be linked to neither LDLR nor APOB genes. These data were confirmed by the exclusion of both genes through direct haplotyping in three families. Our results demonstrate that the relative contributions of LDLR and APOB gene defects to the disease are very different. Furthermore, our results also show that genetic heterogeneity is, generally, underestimated in ADH, and that at least three major groups of defects are involved. At this point, the contribution of the recently mapped FH3 gene to ADH cannot be assessed nor its importance in the group of 'non LDLR/non APOB' families.

The aim of the present study was to search in type IIb hyperlipidemic patients for putative concomitant effects of simvastatin on the physicochemical characteristics of low density lipoproteins (LDL) and high density lipoproteins (HDL), as well as on the activities of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) that were determined in both endogenous lipoprotein-dependent and endogenous lipoprotein-independent assays. In a double-blind, randomized trial, patients received either placebo (one tablet/day; n = 12) or simvastatin (20 mg/day; n = 12) for a period of 8 weeks after a 5-week run-in period. Simvastatin, unlike placebo, reduced the lipid and apolipoprotein B contents of the most abundant LDL-1, LDL-2, and LDL-3 subfractions without inducing significant changes in the overall size distribution of LDL and HDL. Whereas simvastatin significantly increased PLTP activity in an endogenous lipoprotein-dependent assay (P < 0.01), no variation was observed in a lipoprotein-independent assay. Simvastatin significantly decreased plasma CETP activity in an endogenous lipoprotein-dependent assay (P < 0.01), and the reduction in plasma cholesteryl ester transfer rates was explained by a 16% drop in CETP mass concentration (P < 0.01). In contrast, the specific activity of CETP was unaffected by the simvastatin treatment reflecting at least in part the lack of significant alteration in plasma triglyceride-rich lipoprotein acceptors. The simvastatin-induced changes in plasma CETP mass levels correlated positively with changes in plasma CETP activity (r = 0.483, P = 0.0561), in total cholesterol levels (r = 0.769; P < 0.01), and in LDL-cholesterol levels (r = 0.736; P < 0.01). Whereas the observations suggest that simvastatin might exert concomitant beneficial effects on plasma CETP and LDL levels, neither plasma cholesteryl ester transfer activity nor plasma phospholipid transfer activity appeared as the main determinants of the LDL and HDL distribution profiles in type IIb hyperlipidemic patients.

In this study, we first characterized the lipoprotein components of serum samples obtained from a group of well-controlled diabetic patients and from healthy subjects in fasting and postprandial states. We then explored some aspects of reverse cholesterol transport in the same population. Patients showed high levels of fasting triglycerides, postprandial triglyceride responses and LpC-III levels (3.18+/-0.86 vs 2.17+/-0.54 mg/dl, P < 0.001). There were also positive correlations between LpC-III and fasting triglycerides (r = 0.82, P < 0.001), total triglyceride area (r = 0.75, P < 0.001) and incremental triglyceride area (r = 0.54, P < 0.001). HDL-C and apo A-I were significantly decreased in diabetic patients due to a selective reduction in LpA-I subfraction, whose antiatherogenic role is generally accepted (37.4+/-8.0 vs 49.2+/-12.5 mg/dl, P < 0.001). In addition, HDL from patients proved to be triglyceride enriched and cholesteryl ester depleted, alterations which were further amplified in the postprandial state. The molar ratio HDL-C/apo A-I + apo A-II, already defined as a predictor of apo A-I fractional catabolic rate, was significantly diminished in the patient group (15.1+/-2.2 vs 20.8+/-3.3, P < 0.001), thus suggesting an accelerated catabolism of apo A-I. For the first time, we describe here the presence of a small apo A-I-containing particle, isolated by two-dimensional electrophoresis and characterized by immunoblotting, only in samples from diabetic patients. This particle that we named pre-beta0, has an apparent molecular weight of 40 kDa. As regards the capacity of serum samples to promote cholesterol efflux from [3H]cholesterol-labeled Fu5AH rat hepatoma cells, patient samples were found to induce significantly lower cholesterol efflux than controls only in the postprandial state (21.2+/-3.3 vs 23.8+/-1.8%, P = 0.012). The presence of pre-beta0 in samples from diabetic patients might therefore be associated to an altered capacity of these serum samples to promote cellular cholesterol efflux. Overall, these abnormalities may contribute to a delay in the reverse cholesterol transport pathway in type 2 diabetic patients.

This review proposes reinvestigation of a topic studied in the author's laboratory over the last decades concerning the age-dependent modifications of the vascular extracellular matrix (ECM) as related to atherogenesis and its recognized risk-factors: blood lipids, lipoproteins. Most salient previous results are confronted with recent publications in this field. Age-dependent modifications of the vascular wall discussed in this review include upregulation of elastolytic enzymes, demonstrated for the first time in the vascular wall in this laboratory, matrix biosynthesis and receptor function. The progressive deposition of lipids in elastic tissues as well as the addition of lipoproteins or lipids to cell and organ cultures were shown to modify matrix biosynthesis and upregulate elastase expression. Lipid-elastin interactions exhibit a great deal of specificity as shown by the nature and amount of lipids accumulating in elastin in vivo and in vitro. Recent epidemiological studies (the EVA study) enables the confrontation of blood lipid parameters with matrix related components (serum elastase and inhibitors, elastin peptides, fibronectin) in the same blood samples. The elastin laminin receptor present on vascular cells was shown to trigger NO dependent vasodilation, and downregulation of cholesterol synthesis. Both of these functions decrease or disappear with age except the upregulation of elastase release which is preserved and increased. Recent experiments extended these findings to T-lymphocytes present also in the atherosclerotic plaque. Finally several recent publications are analyzed which give more precision on the cellular mechanisms underlying the above-described modifications.

The aim of our study was to determine whether the minor polar components of virgin olive oil could have favorable effects (1) on fasting and postprandial lipid profile and (2) on low-density lipoprotein (LDL) composition and susceptibility to oxidation in vitro. Ten normolipidic subjects were included in a crossover study (two diet periods of 3 weeks) and received either virgin olive oil (OO diet) or oleic acid rich sunflower oil. An oral fat load was performed at the end of each period. The plasma lipid levels were not significantly different after both diets in the fasting and postprandial states. A few minor variations of the LDL composition were observed only in the postprandial lipemia, and they were different after both diets. The LDL oxidation susceptibility was evaluated by the formation of conjugated dienes. With LDL isolated in the fasting state, the diene production decreased (p = 0.0573) only after the OO diet. The dienes determined at time 0 and the maximal dienes obtained during the oxidation reaction decreased (p = 0.0145 and p = 0.0184, respectively) only after the OO fat load. Nevertheless, the diene production decrease was not significant (p = 0.0848). Our results suggest a mild effect of minor components of virgin olive oil related to a decrease of LDL susceptibility to oxidation; further analyses are necessary to give clear conclusions about their role.

Plasma cholesteryl ester transfer protein (CETP) activity, evaluated by the transfer of radiolabeled cholesteryl esters from a tracer dose of tritiated HDL to the plasma apolipoprotein B-containing lipoproteins, was significantly higher in patients with untreated idiopathic nephrotic syndrome (n = 15) than in normolipidemic control subjects (n = 22) (81.5 +/- 8.4 versus 43.1 +/- 3.1 micrograms CE.mL-1.h-1, respectively; P < .001). The increased CETP activity in nephrotic plasma was explained by a significant rise in both the CETP mass concentration (3.2 +/- 0.2 versus 2.1 +/- 0.1 mg/L; P < .001), and the specific CETP activity, calculated as the ratio of CETP activity to CETP mass (25.3 +/- 1.7 versus 20.4 +/- 1.6 micrograms CE.mg-1.h-1; P < .05). Elevated CETP activity in nephrotic patients was shown to be associated with a significant decrease in the mean size of LDL (24.4 +/- 0.5 versus 26.3 +/- 0.5 nm; P < .0001) as well as in the relative abundance of HDL2a (29.6 +/- 1.6% versus 34.8 +/- 1.1%; P < .05). The nephrotic syndrome was characterized by a significant increase in the relative proportion of lipoprotein-bound nonesterified fatty acids (NEFAs) (35.4 +/- 7.7% versus 7.6 +/- 3.0% of total; P < .01), leading to a significant increase in the electronegative charge of LDL (-4.3 +/- 0.1 versus -3.9 +/- 0.1 mV; P < .05) and HDL (-11.5 +/- 0.1 versus -11.1 +/- 0.2 mV; P < .05). Compared with native, non-supplemented plasma, removal of lipoprotein-bound NEFAs by addition of fatty acid-poor albumin to total plasma from nephrotic patients or control subjects significantly decreased CETP activity and specific CETP activity. Specific CETP activity no longer differed between nephrotic and control groups after albumin supplementation (19.7 +/- 1.5 versus 17.7 +/- 1.5 micrograms CE.mg-1.h-1; NS). It is concluded that, in addition to elevated CETP mass concentration, lipoprotein-bound NEFAs, by increasing the negative electrostatic charge of nephrotic lipoproteins, can facilitate the CETP-mediated neutral-lipid transfer reaction in total plasma from nephrotic patients.

1. The common association of obesity, diabetes mellitus and hyperlipidaemia may have a primary aetiological basis. Insulin resistance has been postulated as a possible cause, but defects in the plasma transport of triacylglycerol or fatty acids could also be primary determinants. 2. We have therefore studied 18 patients with diabetes mellitus, obesity and severe hypertriglyceridaemia for defects of a key protein involved in the clearance of plasma triacylglycerols, lipoprotein lipase. 3. DNA was prepared from leucocytes of 18 patients with the above syndrome, and exons encoding lipoprotein lipase were amplified by PCR. The products were sequenced using the dideoxy chain-termination method. 4. Eight of the subjects were found to possess genetic variants at the lipoprotein lipase gene locus. These were: (a) G579-->A, V108V; (b) G818-->A, G188E; (c) C829-->T, R192; (d) A1127-->G, N291S; (e) C1308-->G, F351L; (f) C1338-->A, T361T; and (g) C1595-->G, S447. Three of these, (c), (e) and (f), have not hitherto been described. Variant (f), appears to be a population polymorphism whose allele frequency in normolipidaemic diabetics was found to be 0.12 (162 chromosomes studied). The others are all rare at frequencies of < 0.01 and may contribute to the phenotype by impairing clearance of plasma triacylglycerols. 5. We conclude that genetic variants at the lipoprotein lipase locus occur commonly in subjects with this syndrome (four out of 18 subjects with probably functional mutants) and may affect the individual's response to obesity and diabetes mellitus for the development of lipaemia.

In vitro data suggested that albumin is a key factor controlling apolipoprotein (apo) synthesis by hepatocytes. Studies in analbuminemic rats have shown an increase in secretion of apoB-containing lipoprotein from the liver. We studied the kinetic aspects of apoB- and apoAI-containing lipoprotein metabolism in two sisters with analbuminemia using a constant 14-hour infusion of leucine labeled with stable isotopes. Compared with control subjects, total cholesterol was higher in the two patients (432 and 461 versus 155 +/- 14 mg/dL), as was apoB (257 and 230 versus 72 +/- 7 mg/dL). Triglycerides were slightly increased (134 and 105 versus 89 +/- 9 mg/dL), whereas apoAI was lower (109 and 105 versus 124 +/- 6 mg/dL). VLDL-apoB production was higher, as was the production of IDL-apoB and LDL-apoB (32.8 and 36.0 versus 24.8 +/- 5.9, 32.1 and 27.2 versus 16.4 +/- 2.3, and 14.1 and 17.6 versus 10.3 +/- 1.2 mg.kg-1.d-1, respectively). The fractional catabolic rate of all the apoB-containing lipoproteins was decreased (0.23 and 0.37 versus 0.48 +/- 0.05, 0.27 and 0.28 versus 0.62 +/- 0.08, and 0.012 and 0.009 versus 0.022 +/- 0.002.h-1, respectively). A similar mechanism could explain the dyslipidemia observed in other conditions associated with low albumin levels, such as nephrotic syndrome.

Oxidative modifications of lipoproteins could contribute to the development of atherosclerosis, but the influence of dietary fats on high density lipoprotein (HDL) oxidative modification is unknown. This study was designed to determine whether a diet rich in oleic acid could modulate the oxidative modification of HDL3. Twenty two healthy men were randomly placed on a 32-wk crossover study of an oleic acid rich diet supplied by a variant of sunflower oil vs a linoleic acid rich diet provided by conventional sunflower oil. Plasma HDL3 obtained after the diet rich in oleic acid showed a significantly higher oleic acid content in the phospholipid than lipoprotein isolated after the linoleic acid rich diet. HDL3 isolated after the oleic acid rich diet had lower values of thiobarbituric acid reactive substances (TBARS) than HDL3 obtained after the linoleic acid rich diet both for native (mean +/- SE; 0.24 +/- 0.02 vs 0.42 +/- 0.08 nmol MDA/mg protein; p < 0.01) and copper oxidized HDL3 (0.75 +/- 0.06 vs 0.95 +/- 0.07 nmol MDA/mg protein; p < 0.01). Indeed, TBARS for native HDL3 were negatively correlated with the oleic acid to linoleic acid ratio and positively with the percentage of linoleic acid in their phospholipids. Interestingly, HDL3 after both diets had similar antioxidant vitamins A and E content. HDL3 overall composition and fluidity were similar after the two diets. Moreover, HDL3 obtained after both diets produced identical [3H] free cholesterol efflux from human monocyte-derived macrophages (29%) and fibroblasts (26%). In conclusion, HDL3 rich in oleic acid was less easily oxidized regardless of the content of antioxidants such as vitamins A and E. Therefore, dietary monounsaturated fatty acid prevent the oxidative modification of lipoproteins.

1. Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction. 2. This study was designed to evaluate the effect of lipid-lowering drugs on ubiquinone (coenzyme Q10) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio. 3. Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels > 6.0 mmol l-1) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects. 4. Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls (P < 0.05 and P < 0.001). The difference was not significant between fibratetreated patients and untreated patients. 5. Ubiquinone serum levels were lower in statin-treated patients (0.75 mg l-1 +/- 0.04) than in untreated hypercholesterolaemic patients (0.95 mg l-1 +/- 0.09; P < 0.05). 6. We conclude that statin therapy can be associated with high blood lactate/ pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.

The association between acute pancreatitis and severe hypertriglyceridemia has long been recognized. We report two cases of severe primary hypertriglyceridemia (types 1 and V) with recurrent acute pancreatitis. In both patients, observance of appropriate diet and drug therapy was insufficient. Recurrent episodes of pancreatitis were precipitated by dietary fat or alcohol abuse. A plasmapheresis was performed every 4 weeks to decrease the incidence of pancreatitis. It appears that plasmapheresis is a safe and highly effective method for quickly removing serum triglycerides. Moreover, plasma-pheresis may be useful for preventing acute pancreatitis.

Hypercholesterolemia associated with analbuminemia, an inherited disease manifesting low plasma albumin concentration, is characterized by enhanced LDL cholesterol levels and reduced HDL cholesterol levels. In addition, compared with normal counterparts, the esterified cholesterol:triglyceride ratio tends to be higher in analbuminemic apoB-containing lipoproteins and lower in analbuminemic HDL. The aim of the present study was to investigate the mechanism that may account for the association of a hypoalbuminemic state with alterations in the concentration and composition of plasma lipoprotein fractions. To this end, endogenous cholesterol esterification activity, phospholipid transfer activity, and cholesteryl ester transfer activity were measured in total plasma from three analbuminemic patients and five control subjects. Whereas endogenous cholesterol esterification and phospholipid transfer rates were not significantly affected in analbuminemia, the transfer of radiolabeled cholesteryl esters from HDL toward apoB-containing lipoproteins was constantly higher in analbuminemic plasmas than in normal control plasma (473.6+/-107.3% x h(-1) x mL(-1) versus 227.5+/-84.0% x h(-1) x mL(-1), respectively; P=.036). The rise in cholesteryl ester transfer protein (CETP) activity in analbuminemic plasma was due to a significant increase in the transfer of radiolabeled cholesteryl esters toward LDL but not toward the triglyceride-rich lipoproteins. The CETP mass was higher in analbuminemic patients than in control subjects, but the difference did not reach the significance level (5.18+/-0.82 mg/L versus 3.13+/-1.19 mg/L respectively; P=.07). Since abnormally elevated nonesterified fatty acid (NEFA) levels were shown to be associated with analbuminemic lipoproteins, mostly LDL, the direct role of lipoprotein-bound NEFA in enhancing CETP activity was suspected. In support of this view, supplementation of total plasmas with fatty acid-poor albumin was shown to reduce CETP activity to a significantly greater extent in analbuminemic plasmas than in normal control plasma. It is concluded that hyperlipidemia associated with the hypoalbuminemic state can relate, at least in part, to the combined effect of CETP and NEFA in promoting the transfer of cholesteryl esters from the antiatherogenic HDL toward the proatherogenic apoB-containing lipoproteins.

The high incidence and prevalence of coronary heart disease in diabetes mellitus is clearly established. The usual lipid pattern found in type II diabetic patients is a moderate increase in fasting triglyceride levels associated with low HDL cholesterol levels. These abnormalities are further amplified in the postprandial state. To study the effect of these alterations on reverse cholesterol transport, we isolated lipoprotein containing apoA-I but not apoA-II (LpA-I) particles by immunoaffinity chromatography from the plasma of well-controlled type II diabetic patients and nondiabetic matched control subjects. Different parameters involved in this antiatherogenic pathway were measured in both fasting and postprandial states. Diabetic patients had reduced levels of LpA-I particles that were protein enriched and phospholipid depleted. Gradient gel electrophoresis showed that control LpA-I particles had five distinct populations, whereas diabetic particles lacked the largest one. LpA-I isolated from diabetic plasma exhibited a decreased capacity to induce cholesterol efflux from Ob 1771 adipose cells both in fasting (15.1 +/- 10.0% versus 7.5 +/- 2.7%, P < .05) and postprandial (17.7 +/- 11.2% versus 7.7 +/- 3.9%, P < .05) states, whereas only control particles showed significantly higher ability to promote cholesterol efflux after the test meal (P = .02). Lecithin:cholesterol acyltransferase activity measured with an exogenous substrate showed a 54% increase and an 18% decrease postprandially for control subjects and patients, respectively. Thus, the different abnormalities found in the fasting state were further amplified in the postprandial situation. This resulted in LpA-I particles with aberrant size and composition and decreased ability to accomplish their antiatherogenic role in type II diabetic patients.

Fluvastatin monotherapy up to 40 mg/day over 52 weeks in patients with primary hypercholesterolemia decreased plasma low density lipoprotein cholesterol (LDL-C) by 28%, with varying decreases in plasma triglycerides and increases in high density lipoprotein cholesterol (HDL-C). Patients completing the 52-week study participated in a further trial to assess whether the efficacy of fluvastatin (20-40 mg/day), either as monotherapy or in combination with cholestyramine (CME; 4-16 g/day), taken at least 4 hours prior to fluvastatin, is sustained for up to 3 years. Patients were assessed every 12 weeks on average for safety and efficacy, the latter being calculated as a percent change from baseline of lipids or lipoproteins. During the second year (endpoint up to week 104), 147 patients received monotherapy (estimated mean dose, 30.2 mg/day) and 127 received additional CME (38.1 mg/day fluvastatin plus 10.1 g/day CME). During the third year (endpoint up to week 156), 140 patients received monotherapy (32.5 mg/day) and 67 received additional CME (39.3 mg/day fluvastatin plus 10.3 mg/day CME). Statistically significant reductions in mean total cholesterol and LDL-C and increases in mean HDL-C were achieved in both treatment groups and maintained throughout the study. A significant reduction in triglyceride levels was only observed at the second year endpoint in patients receiving monotherapy (-10.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

Following a 6-week placebo period, 134 patients with low density lipoprotein cholesterol (LDL-C) > or = 160 mg/dL and plasma triglyceride < or = 400 mg/dL, despite following a standard lipid-lowering diet, were randomized to double-blind, double-placebo treatment with fluvastatin (22 women, 46 men; age 21-71 years) or pravastatin (25 women, 41 men; age 19-76 years). Fluvastatin at 40 mg and pravastatin at 20 mg were given for the first 4 weeks, both once daily with the evening meal. For the following 12 weeks, fluvastatin at 40 mg twice daily and pravastatin at 40 mg once daily were given with the evening meal. Both drugs were equally effective in lowering LDL-C after 4 weeks of treatment (-24.0% with fluvastatin, -24.1% with pravastatin) but, after 16 weeks, LDL-C reduction was -30.4% with fluvastatin and -26.6% with pravastatin. This further lowering of LDL-C between week 4 and week 16 was significant (p < 0.001) for fluvastatin but not pravastatin. Adverse events were reported by 23 fluvastatin patients and 22 pravastatin patients: 3 patients in each group withdrew from the study because of these. No notable abnormalities in levels of alanine or aspartate aminotransferase values (defined as > 3 times the upper limit of normal on 2 consecutive occasions) or of creatine phosphokinase (defined as > 10 times the upper limit of normal on any occasion) were observed in either treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein abnormalities [mainly high levels of very-low-density lipoprotein triglycerides (TG) and low levels of high-density lipoprotein cholesterol] increase the risk of cardiovascular disease in Type 2 diabetic patients. Moreover, only fasting TG and central obesity appear to independently predict mortality from CAD in glucose-intolerant and diabetic subjects. It is noteworthy that fasting lipid levels in these patients are often relatively unaffected, and that plasma TG may remain < 2 g/l, the cutoff point currently considered to define moderate hypertriglyceridemia. Our study of postprandial lipaemia shows that lipid intolerance (a greater increase of postprandial TG and a slower return towards basal levels) was almost always present in these patients, enabling us to detect atherogenic changes in plasma lipoproteins. Preliminary results indicate that fenofibrate treatment in Type 2 diabetes under optimised metabolic control improves not only fasting lipid levels but also postprandial lipaemia and associated abnormalities in lipoprotein levels and composition.

The effect of gemfibrozil treatment on very low (VLDL) and low (LDL) density lipoprotein subfractions has been investigated in 9 moderate hypertriglyceridemic (HTG) patients (triglyceride (TG) levels 237-426 mg/dl). Three VLDL subfractions, VLDL1 (Sf 175-400), VLDL2 (Sf 100-175) and VLDL3 (Sf 20-100) and 4 LDL subspecies, LDL1 (1.023-1.028 g/ml), LDL2 (1.029-1.037 g/ml), LDL3 (1.038-1.049 g/ml) and LDL4 (1.050-1.062 g/ml) were prepared by density gradient ultracentrifugation. High density lipoprotein (HDL) chemical composition and lipolytic activities after heparin injection were also determined. Gemfibrozil induced a net decrease in VLDL1 and VLDL2 concentrations (P < 0.01). Cholesteryl ester (CE) weight percent was significantly reduced in both VLDL1 and VLDL2 subfractions. VLDL3 concentration and composition were not changed by the treatment. Lipoprotein lipase (LPL) activity was reduced in HTG patients (P < 0.05). After treatment, LPL activity increased (P < 0.05) but remained lower than in control, normotriglyceridemic (NTG) subjects. Furthermore, gemfibrozil increased HDL cholesterol (P < 0.05) and normalised the elevated HDL2 and HDL3 TG content. The increase of LDL cholesterol, often observed after gemfibrozil treatment, was due to a rise in the LDL2 subfraction (1.029 < d < 1.037 g/ml), the main fraction present in control subjects. However, despite the significant decrease of total plasma TG (329 mg/dl vs. 174 mg/dl), LDL3 subfraction (1.038 < d < 1.049 g/ml) was not reduced.

We explored the effects of oral glycerol administration (20 g) alone or in combination with a mixed meal on postprandial lipids, free fatty acids, high-density lipoprotein cholesterol and retinyl palmitate. We also tested the meal alone as a control. The metabolic behavior of 13C-labelled glycerol, mainly its incorporation into triglycerides and glucose, was also investigated. The tests were performed on 13 healthy subjects aged 20-56 years (mean 32.1 +/- 10.8). Glycerol administration alone induced a decrease in plasma free fatty acid levels. When glycerol was given with the meal, it was absorbed faster and postprandial triglyceride levels were higher compared to the meal alone (p < 0.05). An earlier and higher peak of retinyl palmitate was also observed when comparing the glycerol and mixed meal test to the mixed meal alone. No significant effect was observed on total, high-density and low-density lipoprotein cholesterol. These results suggest that the glycerol-induced increase in postprandial triglyceride levels is probably due to an increase in chylomicron synthesis and perhaps to the stimulation of intestinal glycerol kinase activity. 13C-labelled glycerol administration showed a more important glycerol incorporation in lipoproteins with a density range of < 1.006 during the test with glycerol alone as compared to the test with glycerol and a mixed meal, suggesting that the rate of glycerol incorporation into lipoproteins depends on the availability of other substrates.

1. In this randomised, double-blind, placebo-controlled study, the efficacy of four dosages of fluvastatin (2.5, 5, 10 and 20 mg day-1) were assessed in 431 patients with primary hypercholesterolaemia recruited in 17 centres. 2. Following an 8-week dietary stabilisation phase and a 6-week placebo phase, the patients were randomised to receive placebo or fluvastatin 2.5, 5, 10 or 20 mg once daily at night for a period of 6 weeks. 3. Total cholesterol, beta-quant LDL-C, and the beta-quant LDL-C/HDL-C ratio were significantly reduced by all doses of fluvastatin, and HDL-C was significantly increased by the 10 mg and 20 mg doses. Fluvastatin 20 mg day-1 also significantly decreased TG and Lp(a):B levels. 4. Fluvastatin was well tolerated during the study, and relatively few biochemical or haematological abnormalities occurred. 5. Of the dosages tested, 20 mg fluvastatin day-1 is the optimal hypolipidaemic dose.

In this long-term (52-week) open-label extension to an earlier randomized, multicenter, double-blind, placebo-controlled, dose-finding trial, 381 patients with primary hypercholesterolemia received fluvastatin at increasing doses of 10 to 40 mg/day to achieve plasma low-density lipoprotein (LDL) cholesterol normalization, according to the European Atherosclerosis Society guidelines. The aim of the extension study was to assess the long-term efficacy, safety, and tolerability of fluvastatin. After 52 weeks of therapy, 75% of patients were receiving fluvastatin at 40 mg/day (mean dose: 36 +/- 8 mg/day). The mean percent change in LDL-cholesterol levels from baseline was -24.8% (p < 0.001), and 82.6% of patients achieved an LDL-cholesterol reduction of > or = 15%. In patients in the lowest baseline quintile, high-density lipoprotein-cholesterol levels were significantly (p < 0.001) increased by 8.8% whereas, in the highest baseline quintile, triglycerides were significantly (p < 0.001) reduced by 15.3%. Plasma lipoparticle (a) [Lp(a)]:B levels were also significantly reduced (-38.6%; p < 0.001). Fluvastatin was considered to be well tolerated by the majority of patients by both patients and investigators. The most frequently reported adverse event was abdominal pain. Notable biochemical abnormalities were rare. In conclusion, the results of this extension study indicate that fluvastatin at dosages of 20-40 mg/day is effective and well tolerated in patients with primary hypercholesterolemia and is accompanied by no particular problems of safety.

Familial hypobetalipoproteinemia is caused by apolipoprotein (apo) B gene mutations and is frequently associated with a truncated apo-B protein in the plasma. Homozygosity for mutations yielding a truncated apo-B is extremely rare; fewer than five true homozygotes have been described in the world's literature. These patients typically have normal levels of triglycerides and virtually absent low density lipoprotein (LDL) cholesterol. The clinical status of these patients is variable, ranging from asymptomatic in two homozygotes who synthesized a truncated apo-B (apo-B87) to severe neurological disease resulting from vitamin E deficiency in a homozygote who synthesized a shorter apo-B (apo-B50). In this report, we describe a 48-year-old female homozygous for a nonsense mutation resulting in an even shorter apo-B, apo-B45.2. Although this individual had virtually no LDL cholesterol, she was asymptomatic and had normal plasma levels of vitamin E. This case demonstrates that homozygosity for an apo-B mutation associated with a relatively short apo-B truncation can be completely asymptomatic.

Lipoprotein abnormalities, mainly high very-low-density lipoprotein (VLDL) and low high-density lipoprotein (HDL) levels, increase the risk of coronary heart disease (CHD) in type II diabetic patients. To investigate the relationship between these lipoprotein abnormalities and the postprandial (PP) lipid-clearing capacity, triglyceride (TG) and hormonal levels were determined hourly up to the 4th hour after a mixed meal containing 32.5 g lipids/m2 body surface in 14 treated non-obese type II diabetic patients with adequate nutritional and glycemic control (hemoglobin A1C [HbA1C] < 7%) and in 12 healthy subjects matched for age, sex, and body mass index (BMI). Mean cholesterol levels did not differ between patients and controls, with fasting TG moderately increased in diabetics (140 +/- 70 v 66 +/- 34 mg/dL, P < .01). Whereas fasting TG levels in patients showed a continuous distribution from 55 to 250 mg/dL, postprandial TG clearly identified two different subgroups. A "high-responder" or hypertriglyceridemic subgroup (HTG) showed PP TG levels significantly higher than control levels (290 +/- 62 v 106 +/- 41 mg/dL, P < .001), with higher fasting TG as well (181 +/- 52, P < .01), whereas both fasting and PP TG levels were not different from control levels in the normotriglyceridemic (NTG) diabetic subgroup. The magnitude of the PP triglyceridemic area showed a negative correlation with HDL2 cholesterol (r = .66, P < .001) and a positive correlation with PP HDL2 TG enrichment (r = .80, P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Familial xanthomatous hypercholesterolemia is a metabolic disorder associated with high LDL levels attributed to a familial defect in LDL receptor activity. We have previously shown that hyperlipoproteinemia of WHHL rabbits, considered to be a model for heritable hypercholesterolemia, was at least partly of exogenous origin. We have though studied retinyl palmitate (RP) levels 12 h after a standardized mixed meal as a simple test to detect abnormalities of intestinal-derived lipoprotein clearance in 22 familial hypercholesterolemic patients with xanthomatosis (13 of them treated by simvastatin, an HMGCoA reductase inhibitor, and 9 not treated), as compared to a control group (n = 12). Total and LDL cholesterol, plasma triglyceride and apo B levels were significantly higher in patients when compared to controls. Mean RP levels appeared higher in familial hypercholesterolemic patients, when compared to controls, with 6 among 22 patients showing clearly high vitamin A levels and 4 borderline values, whereas high triglyceride levels (> 2 g/l) were detected in only 1 patient. No patients within the group with high vitamin A levels showed an apo E2/E2 phenotype. Vitamin A levels correlated with plasma triglycerides in the whole group of subjects (r = 0.50, p < 0.05). No difference was observed in vitamin A distribution between treated and untreated hypercholesterolemic patients. Our results indicate that the clearance of RP-labeled intestinal lipoproteins is delayed in some xanthomatous familial hypercholesterolemic patients as compared with that of controls. These findings suggest that familial xanthomatous hypercholesterolemia may be heterogenous concerning physiopathological mechanisms inducing hyperlipidemia.

The present study attempted to characterize the distribution of cyclosporin A (CsA) among the lipoprotein fractions, very-low-, intermediate-, low-, and high-density (VLDL, IDL, LDL, and HDL, respectively) in the plasma of patients awaiting heart transplantation and the influence of plasma lipid constituents on the pharmacokinetics of CsA. Major fractions of a therapeutic concentration of CsA were found in HDL and in LDL. In addition, plasma lipid concentrations (total cholesterol, triglycerides, phospholipids, VLDL-cholesterol--TC, TG, PL, VLDLc, respectively) are positively correlated with the CsA distribution within the LDL fraction, and negatively correlated with the CsA distribution within the HDL fraction. Thus, the percentage of CsA in each type of lipoproteins was shown to vary with the lipid levels among individuals. A significant negative correlation was found between apparent distribution volume at steady state (Vss) in plasma and TC, PL, and LDLc and between the area under the curve measured in blood (AUCB) for whole blood and PL.

This study was designed to determine whether modifications induced by dietary fats on the high-density lipoprotein3 (HDL3) physicochemical characteristics could affect cholesterol efflux and intracellular cholesterol content, leading to upregulation of low-density lipoprotein (LDL) receptor activity from cultured fibroblasts. Serum HDL3S were obtained from 12 healthy women aged 26 to 49 years who adhered to four 7-week isocaloric diets containing 30% of the caloric intake as fat. Of the total calories, 15.6% of each diet was provided by (1) milk fats, rich in saturated fatty acids; (2) sunflower oil, rich in n-6 polyunsaturated fatty acids; (3) olive oil, rich in monounsaturated fatty acids; and (4) rapeseed oil, rich in n-3 polyunsaturated fatty acids. HDL3 isolated after the monounsaturated fatty acid diet induced the greatest cellular [3H]free cholesterol efflux, reduced the content of intracellular cholesterol, and enhanced 125I-LDL degradation. Univariate regression analyses suggested that the increased capacity of HDL3 to promote cellular [3H]free cholesterol efflux was in part due to its greater fluidity, higher cholesteryl ester content, elevated linoleic to linolenic acid ratio in phospholipids, and its smaller size. In conclusion dietary fats induced physicochemical changes in HDL3, which strongly modulated cellular cholesterol homeostasis in vitro. These data also suggest a novel mechanism by which dietary fats exert their effect on atherosclerosis.

The presence of lecithin:cholesterol acyltransferase (LCAT) deficiency in six probands from five families originating from four different countries was confirmed by the absence or near absence of LCAT activity. Also, other invariate symptoms of LCAT deficiency, a significant increase of unesterified cholesterol in plasma lipoproteins and the reduction of plasma HDL-cholesterol to levels below one-tenth of normal, were present in all probands. In the probands from two families, no mass was detectable, while in others reduced amounts of LCAT mass indicated the presence of a functionally inactive protein. Sequence analysis identified homozygous missense or nonsense mutations in four probands. Two probands from one family both were found to be compound heterozygotes for a missense mutation and for a single base insertion causing a reading frame-shift. Subsequent family analyses were carried out using mutagenic primers for carrier identification. LCAT activity and LCAT mass in 23 genotypic heterozygotes were approximately half normal and clearly distinct from those of 20 unaffected family members. In the homozygous patients no obvious relationship between residual LCAT activity and the clinical phenotype was seen. The observation that the molecular defects in LCAT deficiency are dispersed in different regions of the enzyme suggests the existence of several functionally important structural domains in this enzyme.

This multicenter, double-blind, randomized study was designed to compare the effects of simvastatin (20 mg/d and 40 mg/d) and fenofibrate (400 mg/d) on plasma lipids, lipoproteins, apolipoproteins (apo), and lipoprotein particles defined by their apo composition (Lp A-I, Lp A-II:A-I, Lp E:B, Lp C-III:B) in primary hypercholesterolemia. After 6 and 10 weeks of therapy, both drugs lowered plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apo B. The effect on LDL and apo B was significantly more pronounced for simvastatin (P = .01). Simvastatin increased Lp A-I, but did not change Lp A-II:A-I, while fenofibrate decreased Lp A-I and increased Lp A-II:A-I. Lp E:B and Lp C-III:B were decreased with both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin. This study demonstrates that both drugs have beneficial effects on the parameters positively or negatively correlated with the atherosclerotic risk, with simvastatin being more effective in reducing some of them. These results suggest that the drugs led to different structural modifications of the lipoproteins, which would not be revealed by examination of lipoprotein density classes. These differences are probably related to the different mechanisms of action of the agents.

Clinical expression of atherosclerosis is infrequent among patients with schistosomal hepatic fibrosis (SHF), besides, the latter disease is a disease with many immunological expressions. The aim of the present work was to search for a possible immunological and metabolic interaction which would modulate atherogenic mechanisms. The study was carried out on 31 patients with SHF and 20 non-schistosomal subjects (10 with evident clinical atherosclerosis and 10 without). All investigated subjects were males aged above 40 years, and were subjected to the following: serum lipoprotein pattern, total cholesterol, phospholipids, triglycerides, ApoA, ApoB, IgG, IgM, IgA, C3 + circulating immune complexes (CICs) and passive haemagglutination using S mansoni adult worm antigens. The results showed low levels of blood lipids in patients with SHF especially in those with porto-systemic collaterals; serum levels of IgG and IgM were significantly increased in all patients with SHF, while IgA was only increased in patients with collaterals who in turn showed the least incidence of clinically evident atherosclerosis; serum C3 was increased in patients with clinical atherosclerosis, both schistosomal and non-schistosomal. CICs have been higher in patients with SHF without atherosclerosis while decreased in atherosclerosis patients, both schistosomal and non-schistosomal. Our results may consolidate the view of a protective role of liver affection against atherogenesis as well as the important contribution of the immune mechanisms in this context.

This study compares the effects of fenofibrate and simvastatin in primary hypercholesterolemia, with particular regard to lipoprotein particles, as defined by their apolipoprotein composition: LpAI, LpAII: AI, LpE:B, LpCIII:B. This was a double-blind study in which patients were randomized to 2 groups, one receiving simvastatin 20 mg once daily and the other receiving fenofibrate 200 mg b.i.d., if their total cholesterol and their LDL cholesterol remained above 7.60 mmol/l (300 mg/dl) and 4.95 mmol/l (195 mg/dl) after a 4-week placebo period. Simvastatin dosage was doubled at the end of 6 weeks of therapy if the LDL-cholesterol level remained above 3.55 mmol/l (140 mg/dl). Analyses were done after 6 and 10 weeks of therapy. Apolipoprotein AI was increased significantly only at week 10 with fenofibrate (+7.4%). Simvastatin had a more pronounced effect than fenofibrate on apolipoprotein B. There was a significant difference between drugs at weeks 6 and 10. No change was observed in the LpAII:AI level with simvastatin, whereas fenofibrate increased these particles quite significantly (+13.9 and +22.3%). The drugs had opposite effects on LpAI (+2.5 and +5.6% with simvastatin; -12.8 and -15.1% with fenofibrate). LP E:B (-33.0 and -40.8% with simvastatin; -53.8 and -52.2% with fenofibrate) and LpCIII:B (-23.8 and -31.8% with simvastatin; -35.1 and -43.5% with fenofibrate) were decreased by both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin at week 6. This study suggests that both drugs led to different structural modifications of the lipoproteins, which would not be revealed by total apolipoprotein analysis. These differences are probably related to the mechanisms of action of these drugs.

1. The effects of simvastatin (one of a new class of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors) and fenofibrate on the fatty acid composition of cholesterol esters, phospholipids and triglycerides of different lipoproteins of 15 patients with primary hypercholesterolaemia were compared in a double-blind study. 2. Fenofibrate (300 mg day-1) increased the relative content of saturated fatty acids of cholesterol esters, phospholipids and triglycerides in VLDL, IDL and HDL. It also increased the relative content of monounsaturated fatty acids of cholesterol esters and phospholipids in all fractions and those of triglycerides in VLDL and IDL. In contrast, it decreased the proportion of polyunsaturated fatty acids of cholesterol esters and phospholipids in all fractions and those of triglycerides in VLDL and IDL. The polyunsaturated/saturated (P/S) ratio was reduced in cholesterol esters and phospholipids in VLDL and in phospholipids in IDL by fenofibrate. The drug significantly increased the 18:1w9/18:2w6 ratio in cholesterol esters and phospholipids in VLDL, LDL and HDL, but produced a non-significant increase in the ratio in IDL. 3. Simvastatin (20 mg day-1) produced a significant decrease in saturated fatty acid and an increase in polyunsaturated fatty acid in triglycerides in VLDL. Simvastatin, in contrast to fenofibrate caused a slight decrease in saturated and monounsaturated fatty acids in the three other lipoprotein fractions, and an increase in polyunsaturated fatty acids. The P/S and 18:1w9/18:2w6 ratios were not modified by simvastatin.

Male adult Wistar rats received daily (at 9 a.m. and 5 p.m.) 10 micrograms of zinc-protamine glucagon by subcutaneous injection for 8 days. Plasma cholesterol levels were decreased by 36% in fed rats, 33% in cholesterol-fed rats and by 55% in fasted rats. Lipoproteins were separated into 22 fractions by ultracentrifugation using a density gradient. Glucagon administration decreased the cholesterol content in all lipoproteins except low density lipoprotein (LDL1) (1.006-1.040) and very low density lipoprotein (VLDL) from cholesterol-fed rats. The main decrease (-57 to -81%) was observed in 1.050-1.100 g/mL lipoproteins (LDL2 and HDL2), which contained a large amount of apo E, while HDL3 cholesterol was not affected. Triacylglycerol levels were decreased only in chylomicrons and VLDL (-70%) of fed and cholesterol-fed rats, while plasma and lipoprotein triacylglycerol levels were not changed in fasted rats treated with glucagon. In normally fed rats glucagon administration increased by 42% the fractional catabolic rate of [125I]HDL2 while the absolute catabolic rate appeared to be unchanged. Glucagon seems to be a potent hypolipidemic agent affecting mainly the apo E-rich lipoproteins. Its chronic administration limits lipoprotein accumulation which occurs upon cholesterol feeding.

The effects of a 2-month dietary treatment (1,625 +/- 177 kcal, 40 +/- 2.3% carbohydrate, 35 +/- 3.7% fat, 25 +/- 2% protein, polyunsaturated/saturated fat ratio = 1.02 +/- 0.06) on the overall composition of serum lipids, lipoproteins and the fatty acid composition of cholesterol esters and phospholipids in very low (VLDL), intermediate (IDL), low (LDL) and high (HDL) density lipoprotein in 5 patients with primary familial hypertriglyceridemia type IV were assessed. The data were compared with those for 9 normolipidemic subjects. Treatment decreased serum triglycerides (-52%) and total cholesterol (-12%) due to decrease in free cholesterol (-30%). It produced a significant decrease in all the constituents of VLDL (-58%), but the VLDL remained significantly higher after treatment than those of control subjects. The diet caused a decrease in triglycerides (-16%, -29% and -33%, respectively), and an increase in cholesterol in IDL, LDL and HDL. The IDL level in the treated patients remained significantly higher than in the controls. The LDL cholesterol/HDL cholesterol ratio was unchanged after treatment. The fatty acid compositions of the patients before treatment and the controls were not significantly different. The diet caused a decrease in palmitoleic and oleic acids in the cholesterol ester fraction and an increase in linoleic acid, but this was significant only in VLDL and HDL. The diet decreased the eicosapentaenoic acid but the drop was only significant in IDL and LDL. There was also a decrease in linolenic acid, only significant in IDL. The diet induced only minor changes in the phospholipid fractions. We concluded that a single nutritional regimen can effectively decrease the serum lipids and normalize the lipoprotein composition of type IV hypertriglyceridemic patients.

The chemical composition and the physical properties of lipoproteins (VLDL, LDL and HDL) were studied in two groups of patients: 14 healthy normolipidemic subjects and 15 type IIa familial hypercholesterolemic patients. The steady-state fluorescence anisotropy rs was estimated in lipoproteins by the fluorescence depolarization of two fluorescent probes: the DPH (1,6-diphenyl-1,3,5-hexatriene) and the TMA-DPH (1,4-trimethylammonium phenyl-6-1,3,5-hexatriene). A structured order parameter S was calculated from the DPH fluorescence anisotropy. The flow activation energies were calculated for LDL and HDL from both groups from the Arrhenius plots (log r DPH versus 1/T). By using TNBS (trinitrobenzene sulfonic acid) as a distance control quencher, the two probes were located in the outer shell of LDL. In HDL, TMA-DPH remained at the surface of the particles, while DPH was more deeply embedded in the lipid core. There was no difference in the physico-chemical properties of VLDL between the two groups studied. DPH fluorescence anisotropies were significantly increased in LDL and HDL from the hypercholesterolemic group compared to the control particles (P less than 0.05 and P less than 0.01, respectively). In LDL this modification of the fluorescence anisotropy can be related to a change in the lipid composition of particles. LDL from hypercholesterolemic patients contained significantly less triacylglycerol (P less than 0.01) and more cholesteryl ester (N.S.). Their cholesteryl ester to triacylglycerol ratio was significantly higher. In HDL, there was no difference in chemical composition between the two groups. The increase in DPH fluorescence anisotropy can be related to the presence of smaller particles in HDL from HC group. No difference was noted in the TMA-DPH fluorescence anisotropy at 37 degrees C in the LDL from the two groups. In contrast, TMA-DPH fluorescence anisotropy in HDL from hypercholesterolemic group was significantly higher than in control HDL. The flow activation energy of DPH was also significantly higher in both LDL and HDL from the hypercholesterolemic group than in control group particles. In both LDL and HDL from the control group, DPH fluorescence anisotropy was negatively correlated with TG/protein and TG/PL ratios and positively correlated with the CE/TG ratio. No correlation was observed between lipid composition and DPH fluorescence anisotropy values in hypercholesterolemic particles. The modification in fluidity parameters, especially the increase in the flow activation energies in LDL and HDL from hypercholesterolemic patients, could lead to a restriction of cholesterol movements in these particles. From a physiological point of view, this could represent a loss of functional capacity.

The present study was undertaken to analyze whether the changes induced by dietary manipulations in the chemical composition of HDL, particularly in total phospholipids, phosphatidylcholine and sphingomyelin fatty acid composition, modified their fluidity. 12 healthy women, aged 26-49 years were studied. They consumed, over periods of 5 weeks, various isocaloric diets, each containing 30% of the calories as fat. 15.6% of the total calories were provided successively by olive oil, soybean oil, corn oil, and milk fats. The HDL fluorescence anisotropy was measured with 1,6-diphenyl-1,3,5-hexatriene (DPH) by fluorescence polarization. The HDL from the monounsaturated diet, olive oil, were the most fluid particles. The HDL fluorescence anisotropy was positively correlated with their free cholesterol percentage and negatively correlated with their triacylglycerol content and their triacylglycerol/phospholipid ratio. Moreover, the HDL fluorescence anisotropy was negatively correlated with the percentage of oleic acid in their total phospholipids and particularly in the phosphatidylcholine. These results suggest that the percentages of triacylglycerol and oleic acid in phospholipids of HDL have a fluidifying effect on these lipoproteins.

The effects and safety of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, were investigated alone or in association with cholestyramine in 66 patients with hypercholesterolaemia, in a 1-year study. In type IIa hypercholesterolaemia (41 patients), the association was more effective than simvastatin used alone in lowering total cholesterol (37% vs 29%) and LDL-cholesterol (45% vs 37%). In type IIb hypercholesterolaemia (23 patients), the association simvastatin-cholestyramine did not appear more effective than simvastatin used alone. The decrease of apoprotein B was parallel to the LDL-cholesterol decrease. Apoprotein A1 did not change significantly. The long-term safety of simvastatin was good. No lens opacity was noted. The most serious side-effect in our study was myolysis which occurred in two patients with a marked increase in creatine phosphokinase.

Free and esterified cholesterol in the skin were assayed by gas chromatography after thin layer histochromatographic separation. There were 20 controls of both sexes, 36 subjects with type lla hyperlipoproteinemia, 27 with type IIb hyperlipoproteinemia and 19 with type IV hyperlipoproteinemia. Esterified skin cholesterol levels were higher in women with the type of lla disorder and in subjects with tendinous xanthomas. The levels of esterified skin cholesterol in type II women is not correlated with free skin cholesterol or with total circulating cholesterol; all these parameters are correlated in men. Furthermore, skin cholesterol levels were determined in 15 type II subjects before and after a six month treatment with the anticholesterolemic probucol. Cholesterolemia decreased 10 per cent, free skin cholesterol decreased slightly and esterified skin cholesterol increased significantly, as did the esterified/total skin cholesterol ratio. These data suggest the existence of a relationship between low vascular risk and elevated levels of esterified skin cholesterol (or elevated esterified/total skin cholesterol ratio).

Fibroblasts in culture and leukocytes have been widely used to study fatty acid and lipoprotein cellular metabolism. The present investigations were designed to study the role of nutritional and environmental factors on lipid metabolism in these two types of cells. Leukocytes freshly isolated from human blood and fibroblasts cultured in media enriched in human serum (HS) have relatively similar fatty acid distributions. However, more important differences are observed in fibroblasts cultured in media enriched with HS or with fetal bovine serum (FBS). It is obvious that the quantity and quality of fatty acids are very different in FBS and HS, but intracellular regulation ensures relative homogeneity of saturated (SFA) and monounsaturated fatty acids (MUFA) in the cells, particularly in phospholipids. The first modifications induced by different media (FBS or HS) are detected on cellular growth; the differences seem to be due more to the fatty acid (FA) quantitative supply than to the FA quality of each culture medium. The major modifications in FA composition induced by different culture media concern the polyunsaturated fatty acids (PUFA) of phospholipids, especially the n-6 family. The intracellular linoleic acid level depends on the level in the medium, but intracellular n-6 metabolite levels depend both on the level in the medium and on the growth state of the cells. The n-3 family seems to be less affected by the quality of the medium in our experiment, and the cells maintain a stable docosahexaenoic acid (22:6n-3) level. A higher content of the n-3 family in the medium induces a higher level of eicosa- or docosapentaenoic acid, rather than docosahexaenoic acid itself.(ABSTRACT TRUNCATED AT 250 WORDS)