Interaction of very-low-density lipoprotein isolated from type I (insulin-dependent) diabetic subjects with human monocyte-derived macrophages

Very-low-density lipoproteins (VLDL) (density less than 1.006 g/mL) were isolated from type I (insulin-dependent) diabetic patients in good to fair glycemic control and from age-, sex-, and race-matched, nondiabetic, control subjects. VLDL were incubated with human, monocyte-derived macrophages obtained from nondiabetic donors, and the rates of cellular cholesteryl ester synthesis and cholesterol accumulation were determined. VLDL isolated from diabetic patients stimulated significantly more cholesteryl ester synthesis than did VLDL isolated from control subjects (4.04 +/- 1.01 v 1.99 +/- 0.39 nmol 14C-cholesteryl oleate synthesized/mg cell protein/20 h; mean +/- SEM, P less than .05). The stimulation of cholesteryl ester synthesis in macrophages incubated with VLDL isolated from diabetic patients was paralleled by a significant increase in intracellular cholesteryl ester accumulation (P less than .05). The increase in cholesteryl ester synthesis and accumulation in macrophages were mediated by a significant increase in the receptor mediated, high affinity degradation (2.55 +/- 0.23 v 2.12 +/- 0.20 micrograms degraded/mg cell protein/20 h) and accumulation (283 +/- 35 v 242 +/- 33 ng/mg cell protein/20 h) of 125I-VLDL isolated from diabetic patients compared with VLDL from control subjects. To determine if changes in VLDL apoprotein composition were responsible for the observed changes in cellular rates of cholesteryl ester synthesis and accumulation, we also examined the apoprotein composition of the VLDL from both groups. There were no significant differences between the apoproteins B, E, and C content of VLDL from both groups. We also determined the chemical composition of VLDL isolated from both groups of subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Heterogeneity of very-low-density lipoprotein metabolism in hyperlipidemic subjects

Very-low-density lipoproteins (VLDL) are triglyceride-rich lipoporteins that have been shown, by physicochemical means, to comprise more than one group of particles. Because of the potential atherogenicity of catabolized VLDL, we used the technique of heparin-affinity chromatography to separate VLDL into two classes of particles, one of which appears to contain partly catabolized VLDL. This observation is based on the higher cholesterol/triglyceride and higher apoprotein E/apoprotein C ratios in VLDL particles that are bound to heparin, resembling in this way intermediate-density lipoproteins (IDL), which are certainly derived in the main through VLDL catabolism. Further studies showed separate metabolic characteristics for the unbound and heparin-bound VLDL particles. Radiolabeled whole VLDL or unbound particles were reinjected into seven hypertriglyceridemic subjects and the kinetics studied in serial samples of plasma over the next 18–48 hours. The specific radioactivity-time curves of apoprotein B in the unbound and bound particles showed that the bound particles were derived wholly or partly from the unbound particles and in turn, were the precursors of IDL. This confirmed that heparin-bound VLDL particles represented VLDL undergoing catabolism, although in one subject about one-half of the bound particles appeared to have an origin other than through VLDL catabolism. These studies show that VLDL metabolism is heterogeneous, that the kinetics of total VLDL must be interpreted accordingly, and that the technique of heparin-affinity chromatography can be used for more detailed studies of VLDL.     

Pregnancy, parturition, and lactation in familial homozygous hypercholesterolemia

Lipids and lipoproteins were studied during pregnancy, parturition, and lactation in a subject homozygous for familial hypercholesterolemia and her obligate heterozygote neonate. At the end of the 1st trimester, plasma cholesterol had risen from a preconception level of 530 to 621 mg/dl, C-LDL rose from 489 to 550 mg/dl, C-HDL from 36 to 46 mg/dl, and triglyceride from 23 to 125 mg/dl. During the 2nd trimester, mean cholesterol (615 mg/dl) was significantly higher compared to preconception levels, C-LDL remained elevated at 531, C-HDL was increased to 50 mg/dl, and triglyceride had risen appreciably to 174 mg/dl. In the 3rd trimester, total cholesterol increased to 632 mg/dl, C-LDL rose to 548, triglycerides rose sharply to 275, and C-HDL fell to 30 mg/dl. The neonate's cord blood C-LDL was elevated at 52 mg/dl. Breast milk cholesterol 7 wk postpartum was 6.5 mg/g total milk fat, considerably greater than levels in 14 normals (2.4 ± 0.4). Placental lipid distribution revealed sharply reduced levels of phospholipids, triglyceride, and cholesterol, and increased free fatty acids. The linoleic acid content of the free fatty acid and triglyceride in the placenta (13.8% and 15.1%) was higher than in normal placentas, 10.0% and 10.2%, respectively. The arachidonic acid content of the triglyceride and cholesterol ester in the placenta, 3.5% and 17.8%, were considerably lower than in normal placentas (29.6% and 32.7%). Gross and microscopic examination of placental vasculature did not reveal any evidence for placental insufficiency or accelerated fetal or maternal atherosclerosis.     

Changes in lipoprotein composition in hypertriglyceridemic patients taking cholesterol-free fish oil supplements

Fish oils rich in n - 3 fatty acids (FAs) have been shown to markedly lower levels of very low density lipoproteins (VLDL), but not the low density lipoproteins (LDL) which are derived from VLDL. Changes in the size and chemical composition of lipoproteins may affect their metabolism. In order to examine the effects of n - 3 FAs on lipoprotein metabolism, 6 patients with hypertriglyceridemia were given 6 g n - 3 FAs/day. Plasma lipid and apoprotein (apo A-I, A-II, B, E, C-II, C-III) levels (mg/dl) were measured before and after 4 weeks of treatment. Changes in lipoprotein size were assessed by gel chromatography. n - 3 FAs lowered VLDL cholesterol (58 +/- 35 to 40 +/- 30, P less than 0.01) and total triglyceride (410 +/- 170 to 236 +/- 114, P less than 0.01). In spite of this, LDL cholesterol levels did not decrease, and apo B levels increased (98 +/- 28 to 111 +/- 27, P less than 0.05). HDL cholesterol rose (31 +/- 5 to 34 +/- 7, P less than 0.05). The lipid content of smaller VLDL particles was reduced by over 40%, but the protein content was largely unchanged. Large triglyceride-rich lipoprotein particles were reduced to a greater extent than were small particles. These changes in VLDL particle size and composition may enhance the synthesis of LDL in hypertriglyceridemic patients taking n - 3 FA supplements.     

Selective reduction of cholesterol in HDL2 fraction by probucol in familial hypercholesterolemia and hyperHDL2 cholesterolemia with abnormal cholesteryl ester transfer

Long-term treatment with probucol induced marked regression of xanthoma in patients with both homozygous and heterozygous familial hypercholesterolemia despite a substantial accompanying decrease in high-density lipoprotein (HDL) cholesterol. Furthermore, a close correlation was found between the extent of the regression and the reduction of HDL cholesterol, which suggests that the probucol-induced decrease in HDL may not be an atherogenic change, but may reflect a favorable change for lipoprotein metabolism. The present study also evaluated the effects of probucol on HDL metabolism in patients with familial hyperHDL2 cholesterolemia who had extremely high levels of HDL cholesterol ranging from 130 to 280 mg/dl. Premature corneal opacities were present in 2 patients, 1 of whom also had coronary artery disease despite high HDL cholesterol levels. In the 2 cases, the net transfer of cholesteryl ester from HDL to very low density lipoprotein and LDL was impaired, and low hepatic triglyceride lipase activity was observed, but cholesteryl ester transfer protein was not deficient. Administration of probucol to these patients caused a marked reduction of serum cholesterol, which was accounted for exclusively by a reduction in the HDL2 fraction. The size of the HDL2 particles, which had been much larger, decreased to normal, and the net transfer rate of cholesteryl ester was normalized. In the other 3 cases of hyperHDL2 cholesterolemia, the cholesteryl ester transfer activity was completely deficient. Unlike its effect in the first 2 cases, probucol did not cause any change in lipid and apoprotein in the 3 patients with complete deficiency of cholesteryl ester transfer activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in very low and low density lipoproteins with dietary fat modification

Since VLDL and LDL are involved in atherogenesis, their response to dietary modification was studied in 15 normal male prisoners. A 3-month reference diet (P/S ratio 0.3, daily cholesterol intake 370 mg) was compared with a modified fat diet (P/S 1.0, 250 mg) given for further 3 months. The decrement in serum cholesterol by 32 mg/dl reflected a decrease in VLDL and LDL. It was associated with a decrease in serum apolipoprotein B by 16 mg/dl and in serum apolipoprotein E by 1.2 mg/dl. The decrement in VLDL cholesterol was paralleled by a lowered VLDL apolipoprotein E content. Serum and VLDL triglycerides, HDL cholesterol and the serum apolipoproteins A-I and A-II did not change significantly. One beneficial result of a conventional dietary regimen is lowered LDL with unaffected HDL. Another effect is the apparent modification of VLDL with a decrement of cholesterol and apolipoprotein E-enriched particles.     

Effects of feeding fish oil on the properties of lipoproteins isolated from rhesus monkeys consuming an atherogenic diet

This study examined plasma lipids and lipoproteins of rhesus monkeys fed fish oil incorporated into a highly atherogenic diet containing saturated fat and cholesterol. The animals were fed diets containing 2% cholesterol and either 25% coconut oil (group I), 25% fish oil/coconut oil (1:1; group II), or 25% fish oil/coconut oil (3:1; group III) for 12 months (n = 8/group). Adding menhaden fish oil to the diet increased plasma eicosapentaenoic acid and docosahexaenoic acid and decreased plasma linoleic acid in animals fed the fish oil containing diets. Plasma concentrations of all lipoprotein fractions were decreased in the fish oil groups. VLDL isolated from group I animals exhibited beta-mobility on agarose gels but the VLDL from groups II and III animals did not. The group I VLDL was more highly enriched in cholesteryl ester than was VLDL from groups II and III. Group I LDL had a small but significant increase in cholesteryl ester content compared to group III LDL. No differences in HDL composition were observed in the 3 groups. At least 6 times less apo E was recovered in VLDL, IDL, and LDL from group III animals than from group I animals. Assuming 1 molecule of apo B per lipoprotein particle, there were 50% fewer VLDL, IDL, and LDL particles in group III than in group I animals. Group III also had significantly lower molar ratios of apo E/apo B in VLDL, IDL, and LDL than did group I animals. When VLDL from all 3 groups were incubated with J774 macrophages at equal protein concentrations, only the VLDL from the group I animals stimulated cholesterol esterification. Thus, introducing fish oil into an atherogenic diet reduced the number of VLDL, IDL and LDL particles in plasma by as much as 50%, reduced the cholesteryl ester content of the circulating lipoprotein, and reduced the ability of the VLDL to stimulate cholesterol esterification in macrophages.     

Pravastatin sodium, an inhibitor of HMG-CoA reductase, decreases HDL cholesterol by transfer of cholesteryl ester from HDL to VLDL in Japanese white rabbits

In a recent paper, we reported that pravastatin sodium (pravastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme. A reductase, decreases the concentrations of low density lipoprotein (LDL) cholesterol through an LDL receptor pathway in Japanese White (JW) rabbits, whereas this agent lowers high density lipoprotein (HDL) cholesterol in a manner correlated with a reduction of very low density lipoprotein (VLDL) cholesterol secretion from the liver. In the present study, we administered pravastatin to JW rabbits at 30 mg/kg for 14 days and examined further the mechanisms for the reduction of HDL cholesterol. A striking finding was that the 4-day administration of pravastatin at 30 mg/kg selectively decreased the concentration of HDL cholesterol. Since 4-day administration of pravastatin to JW rabbits did not change the concentrations of hepatic LDL receptor proteins, these receptors were not likely to be involved in the reduction of HDL cholesterol. Another important finding was that pravastatin suppressed VLDL cholesteryl ester (CE) secretion from the liver, but not that of other VLDL lipids and VLDL proteins, indicating that the CE-poor VLDL particles were secreted by the consecutive administration of pravastatin. There were, however, no differences in the levels of VLDL cholesterol between the control and pravastatin-treated groups over the experimental period of 14 days. These observations raised the possibility that the reduction of HDL cholesterol in the pravastatin-treated group was due to the transfer of CE molecules from HDL particles to these CE-poor VLDL particles. Molecular species analysis supported this notion that the VLDL-CE in the pravastatin-treated group was rich in cholesteryl linoleate, indicating that the CE in this group mainly originated from HDL, whereas the VLDL-CE in the control group was rich in cholesteryl oleate, indicating that the CE in this group originated from the liver. The present study suggests that pravastatin lowers HDL cholesterol by transferring CE from these lipoproteins to VLDL in JW rabbits.     

Apolipoprotein E levels in vegetarians

Vegetarians are known to have low lipoprotein lipid and apolipoprotein AI and B levels. Since dietary cholesterol has recently been shown to have important effects on apolipoprotein E (apo E) metabolism, we measured plasma apo E levels in three groups of vegetarians. Group I (n = 36) consumed < 10 mg cholesterol daily and 42% of calories as fat (P:S ratio 2.6). Group II (n = 10) and Group III (n = 18) consumed 97 and 179 mg cholesterol daily, and 35% of calories as fat (P:S ratios 0.7 and 0.9) respectively. Compared to control values, vegetarian plasma cholesterol and triglyceride levels were decreased by 10%–30% and 30%–55%. Plasma apo E levels were decreased equally in all groups by 35% (2.4 ± 0.1 mg/dl versus 3.6 ± 0.1 mg/dl, p < .001). Plasma apo E levels were increased in parallel with lipid levels in pregnant vegetarians but were not different from non-lactating vegetarians in postpartum lactating women. Decreased apo E levels did not correlate with relative body weight, P:S ratio or intake of fat, carbohydrates or protein. Since all vegetarian diets studied were low cholesterol diets, decreased cholesterol intake may contribute to the low apo E levels. The apparent modification of apo E metabolism by vegetarian diets may be important in mediating effects of lipid lowering diets on atherogenesis.     

Effects of a moderate exercise session on postprandial lipoproteins, apolipoproteins and lipoprotein remnants in middle-aged men

Prior moderate exercise reduces postprandial triglyceride concentrations. Its effects on the concentrations, compositions and potential atherogenicity of lipoprotein subfractions were investigated in the present study. Twenty normoglycaemic middle-aged men each underwent two fat tolerance tests (blood taken fasting and for 8 h after a meal containing 80 g fat and 70 g carbohydrate). On the afternoon before one test, subjects performed a 90-min treadmill walk (exercise); no exercise was performed before the control test. Prior exercise significantly reduced postprandial concentrations of chylomicrons (Sf >400) by 28.6% (absolute reduction 14.6 mg dl(-1)), of large VLDL1 (Sf 60-400) by 34.4% (39.7 mg dl(-1)) and of small VLDL2 (Sf 20-60) by 23.0% (9.6 mg dl(-1)). Over 95% of VLDL1 and VLDL2 comprised apolipoprotein (apo) B100-containing particles. Exercise also reduced postprandial remnant-like lipoprotein cholesterol (by 35%) and triglyceride concentrations (by 29%). Postprandial apo CIII/apo B and apo E/apo B ratios in VLDL1 were lower following exercise. Postprandial cholesteryl ester/triglyceride ratios were lower in VLDL1 and VLDL2 and higher in HDL2 following exercise. These data suggest that the effect of prior moderate exercise on VLDL1 is quantitatively greater than its effect on chylomicrons and that, in addition to reducing lipoprotein concentrations, exercise induces compositional changes to lipoprotein species which are likely to influence their metabolism and atherogenicity.     

Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinaemia

Lipoprotein patterns and cholesteryl ester transfer activity (CETA) were examined in 2 patients with familial hyperalphalipoproteinaemia (FHALP). The proband was a healthy 58-year-old Japanese male who had an HDL cholesterol of 7.83 mmol/l (301 mg/dl). His sister's HDL cholesterol was 4.52 mmol/l (174 mg/dl), which suggested that both were homozygous carriers of FHALP. In both subjects HDL showed a high cholesterol/apo A-I ratio and appeared to be a larger-sized particle than normal HDL on agarose gel chromatography. Two of the proband's children showed higher HDL cholesterol levels (1.74 mmol/l, 2.16 mmol/l) than normal, but another 2 children showed normal levels (1.48 mmol/l, 1.40 mmol/l). However, the ratios of HDL cholesterol to total cholesterol and to apo A-I in all children were higher than normal. These data suggest, but do not prove, that all his children were heterozygotes. Apo B levels in all of the family members studied were lower than normal (47-80 mg/dl). Deceased members of the same family had not died from cardiovascular disease. Cholesteryl-ester transfer activity was studied in both patients. When serum or lipoprotein deficient serum (d greater than 1.21) and [3H]cholesteryl ester labelled HDL3 were incubated in the presence of an LCAT inhibitor, there was no evidence of cholesteryl ester transfer from HDL to VLDL and/or LDL, unlike normal subjects. The deficiency of CETA in these patients with FHALP presumably accounted for the increase in particle size and cholesterol enrichment of HDL.     

Effects of high cholesterol high fat diet on plasma lipoproteins in familial hypercholesterolemia

Heterozygous individuals with familial hypercholesterolemia possess about half of the normal numbers of functioning receptors on their cells. This is thought to be responsible for their hypercholesterolemia. In normals, dietary cholesterol increases LDL production and decreases LDL receptor-related LDL clearance, resulting in elevations in LDL cholesterol levels of ～30 mg/dL. To assess the effects of high fat and high cholesterol diets on the lipoproteins of individuals with diminished LDL receptors, three kinds of diets, including ones high in cholesterol, were fed to four patients with familial hypercholesterolemia, in the expectation that diet effects on apoB- or apoE-containing lipoproteins would be exaggerated. The basal diet consisted of 15% protein, 30% fat, 55% carbohydrate, 300 mg/d cholesterol, $\text{P}\text{S}$ ratio 0.4; the high fat diet was identical except that fat calories were 55% and carbohydrate 30%; the high fat-high cholesterol diet was identical with the high fat diet except ～750 or ～1,500 mg/d of cholesterol were added. Each diet was eaten for five weeks at home and for the sixth week at the general Clinical Research Center. Fasting (12–14 hours) plasmas were collected every two weeks for lipoprotein-lipid and apoprotein quantitation. At the end of each period, fasting and 4-hour postprandial samples were analyzed also by zonal ultracentrifugation and gel permeation chromatography. The significant results were as follows: (1) on analysis of fasting samples on the fat + Chol diet, measures of the levels of VLDL (ie, VLDL lipids, VLDL protein on zonal ultracentrifugation, VLDL-associated lipids, and apoE on chromatography) fell; measures of LDL were not consistently changed; and measures of HDL₂ and HDL_c rose. Compositions of VLDL were altered, ie, mass % of triglycerides fell and cholesterol rose. Zonal effluent profiles of VLDL, LDL, HDL₂, and HDL₃ were not altered, nor were gel chromatographic elution patterns of cholesterol, triglycerides, apoB, apoA-I, and apoE, suggesting that the sizes and/or densities of lipoproteins were not altered. Therefore, the numbers of VLDL particles must have fallen and the numbers of HDL₂ and HDL_c must have risen. The nature and magnitude of the changes fell within the range of changes previously observed in normolipidemic subjects. The data indicate that having diminished numbers of LDL receptors did not affect the abilities of these patients to resist diet-induced qualitative or quantitative alterations of their plasma lipoproteins. Clearly other adaptive mechanisms can compensate for the diminished numbers of LDL receptors.     

Effects of prazosin and propranolol on blood pressure and plasma lipids in patients undergoing chronic hemodialysis

Twenty patients receiving hemodialysis who had mild to moderate hypertension were treated with prazosin or propranolol to control predialysis hypertension. Effective blood pressure control was achieved with prazosin (mean dose 8.3 ± 2.2 mg [± standard error of the mean], n = 10) and propranolol (mean dose 123 ± 39 mg, n = 10). Therapy with prazosin did not significantly affect total plasma triglyceride or total cholesterol levels. The level of high-density lipoprotein (HDL) cholesterol tended to increase, but not significantly. However, the HDL₃ subfraction did increase significantly, from 16.3 ± 1.5 to 20.6 ± 1.5 mg/dl (p = 0.05). Propranolol therapy increased plasma triglyceride levels, primarily of the very low density lipoprotein class. HDL cholesterol levels decreased from 44.2 ± 6.7 to 34.7 ± 4.2 mg/dl (p < 0.03). The reduction in the HDL cholesterol levels was attributable to a decrease in HDL₂ cholesterol levels (from 21.3 ± 3.8 to 16.3 ± 3.0 mg/dl, p < 0.04) and HDL₃ cholesterol levels (from 23.0 ± 3.1 to 19.5 ± 2.1 mg/dl, difference not significant). Thus, both prazosin and propranolol are effective in controlling hypertension in patients undergoing hemodialysis. HDL₃ cholesterol levels increased in patients treated with prazosin, but no other significant changes in the plasma lipids occurred. Patients treated with propranolol had a significant decrease in plasma HDL₂ and HDL₃ cholesterol levels.     

Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity

Lipoprotein abnormalities were analyzed in 3 cases of marked hyperalphalipoproteinemia caused by complete deficiency of cholesteryl ester transfer activity. The probands were all men, aged 34, 43 and 48 years, respectively. The serum high density lipoprotein (HDL)-cholesterol levels of these patients were higher than 150 mg/dl (157-254 mg/dl), while serum total cholesterol levels ranged from 227 to 360 mg/dl. Sequential flotation-ultracentrifugation analysis disclosed that low density lipoprotein (LDL)-cholesterol was slightly decreased and that cholesteryl ester accumulated solely in the HDL2 fraction, which was also enriched with apolipoprotein E. Cholesteryl ester transfer activity was completely absent in all of these cases. High-performance liquid chromatography showed a decrease of LDL particle size in combination with a marked enlargement of HDL particle size. Analytical ultracentrifugation disclosed heterogeneity of LDL with the presence of small LDL subpopulations. We conclude that hyperalphalipoproteinemia due to complete deficiency of cholesteryl ester transfer activity is characterized by the presence of both small polydisperse LDL and markedly large HDL enriched with cholesteryl ester and apolipoprotein E.     

Hypertriglyceridemia and hypoalphalipoproteinemia in azoospermic and oligospermic young men: Relationships of endogenous testosterone to triglyceride and high density lipoprotein cholesterol metabolism

Based upon the hypothesis that endogenous testosterone plays a significant role in triglyceride and high density lipoprotein cholesterol metabolism, the specific aim of this study in 9 azoospermic and 10 oligospermic subjects (compared to 20 fertile men) was to examine potential relationships between endogenous testosterone, luteinizing hormone, follicle stimulating hormone, lipids-lipoproteins, and lipoprotein lipases. The azoospermic and oligospermic men had much higher fasting plasma triglyceride levels (mean ± SD; 479 ± 258, 295 ± 119) than did normal controls (105 ± 31 mg/dl, p < 0.001, p < 0.001). The azoospermic and oligospermic subjects also had much lower mean high density lipoprotein cholesterol levels (C-HDL) than normals (27 ± 8 and 29 ± 7 versus 44 ± 7 mg/dl, p < 0.001, p < 0.001). Very low density lipoprotein's (VLDL) in vitro potency to activate lipoprotein lipase (U/mg of VLDL protein) was about one-third normal in the azoospermic subjects (57 ± 26 U/mg), and about one-half normal in the oligospermic subjects (86 ± 27), with values in the normals being 167 ± 58, p < 0.001, p < 0.001. Mean plasma testosterone levels were 3.4 ± 0.7 ng/ml in the azoospermic subjects, considerably lower than mean levels in normals (6.6 ± 2.0, p < 0.001), with intermediate levels in the oligospermic men (5.2 ± 1.7 ng/ml). Pooling the data for the azoospermic, oligospermic, and normal men, plasma testosterone levels were positively correlated with C-HDL (r = .42, p < 0.01) and inversely correlated with triglyceride (r = ?.50, p < 0.001) and very low density lipoprotein cholesterol (r = ?.37, p < 0.02). Plasma testosterone was also positively correlated with lipoprotein lipase activator potency, (r = .45, p < 0.01). These findings suggest that endogenous physiologic testosterone levels may play a role relative to regulation of triglyceride and C-HDL levels in men, and may also affect the hydrolytic susceptability of very low density lipoprotein molecules. Hypertriglyceridemia and low C-HDL levels in azoospermic and oligospermic men mandate quantitation of lipid-lipoprotein levels in infertility clinics to identify men at putatively increased risk for future coronary heart disease.     

Bile sequestrant therapy alters the compositions of low-density and high-density lipoproteins.

Bile sequestrant resins are used to lower the levels of low-density lipoprotein cholesterol in plasma because this may ameliorate atherosclerosis. Yet the levels and compositions of all the lipoproteins may affect atherogenesis. We have previously shown alterations in very-low-density lipoprotein (VLDL) metabolism in response to one of these agents, colestipol HCl. Here we report the effects of colestipol on the composition of low-density and high-density lipoproteins (HDL). Eighteen subjects with type II hyperlipoproteinemia were studied during baseline, diet, and drug periods lasting 2–3 mo. Lipoprotein lipids and apolipoproteins A-I, A-II, and B were measured, and indices of lipoprotein composition were calculated. Colestipol produced significant changes in all lipoproteins. VLDL-triglyceride rose transiently, the magnitude and duration both correlated with pretreatment values (r = 0.84 and 0.76, respectively, both p < 0.001). Low-density (density 1.006–1.063) lipoprotein cholesterol fell below the dietary mean by 28%, but low-density triglyceride fell by only 13% and apolipoprotein B by 17%. Thus, low-density lipoprotein cholesterol/apolipoprotein B ratios decreased (1.9 versus 1.6, p < 0.005). Low-density and very-low-density cholesterol/apoprotein B ratios also decreased significantly. Thus, all the apolipoprotein-B-containing lipoproteins had less cholesterol relative to apolipoprotein B. High-density lipoprotein cholesterol remained unchanged, although transient increases in high-density lipoprotein triglyceride occurred. Apolipoprotein A-I levels remained constant (∼105 mg/dl), but A-II levels fell (from 55 to 45 mg/dl); therefore, $\text{A-I}\text{A-II}$ ratios rose (2.0 versus 2.5, p < 0.001). Thus, alterations in the composition of both high-density and low-density lipoproteins occurred. Colestipol produced changes in lipoprotein composition that may have effects on atherogenesis independent of its effects on lowering plasma cholesterol. Further studies will be needed to determine whether or not these changes are beneficial.     

Black--white differences in plasma lipoproteins in Cincinnati schoolchildren (one-to-one pair matched by total plasma cholesterol, sex, and age).

The suburban, biethnic Princeton School District provided a suitable population of children (ages 6–17) to test the hypothesis that black schoolchildren have higher high density lipoprotein cholesterol (C-HDL), lower low density lipoprotein cholesterol (C-LDL), and lower triglyceride levels than white schoolchildren when pair-matched by total plasma cholesterol, age, and sex. In 194 black-white pairs of male schoolchildren, black children had higher C-HDL (59.5 ± 13.5 versus 54.8 ± 12.7 mg/dl, p < .001), lower C-LDL (105.7 ± 25.8 versus 108.1 ± 26.7, p < .05), and lower triglyceride (60.7 ± 27.2 versus 71 ± 38.1, p < .001). In 222 black-white pairs of female schoolchildren, black girls had higher C-HDL (57.7 ± 13.1 versus 52.0 ± 11.6 mg/dl, p < .001), lower C-LDL (107.4 ± 24.8 versus 109.6 ± 23.3, p < .05, and lower triglyceride (64.0 ± 24.6 versus 80.2 ± 38.6, p < .001). Mean Quetelet indices (weight/height²) did not differ significantly for the black and white males or females. Since, by matching, the pairs did not differ in age, sex, or total plasma cholesterol, and also did not differ by Quetelet, any differences in C-HDL, C-LDL, and triglyceride can be imputed to racial or other unmeasured, racially related environmental differences in the cholesterol-carrying lipoprotein fractions. Persistence of these black-white differences in lipoproteins into adulthood may be associated with a relatively lower risk of coronary heart disease (CHD) in blacks than in whites, for any given total plasma cholesterol level.     

Lipid and lipoprotein distributions in octo- and nonagenarians.

This study focused on 124 octogenarians and 13 nonagenarians to extend data on lipid and lipoprotein distributions into the eighth and ninth decades of life and to assess relationships between lipids, lipoproteins, and longevity. The mean (±SD) ages of the 114 women and 23 men were 85 ± 4 and 84 ± 4 yr, respectively. Mean (±SD) total plasma cholesterol and high density lipoprotein cholesterol (C-HDL) were higher in women than in men, 219 ± 41 and 198 ± 31 mg/dl, 58 ± 16 and 50 ± 13 mg/dl respectively, p<.02. Mean (±SD) low density lipoprotein cholesterol (C-LDL) levels were 132 ± 35 in women, 125 ± 26 mg/dl in men. In women, the 90th percentile levels for total plasma cholesterol, C-HDL, C-LDL, and triglyceride were respectively 269, 79, 180, and 243 mg/dl, with the 10th percentile levels being 164, 36, 85, and 77 mg/dl. For both women and men, total plasma cholesterol was closely correlated with C-LDL, r=.937, .926, p<.01. In the eighth and ninth decades of life, reductions in total plasma cholesterol are probably accounted for by reductions in C-LDL levels, while C-HDL remains stable. Subjects living into the eighth and ninth decades may have lower plasma cholesterol and C-LDL and stable C-HDL, because those with higher C-LDL and/or lower C-HDL have been removed from the distribution by coronary heart disease. Alternatively, some octo- and nonagenarians may also come from kindreds having familial hypobeta- or familial hyperalpha-lipoproteinemia, familial traits associated with increased longevity and reduced CHD morbidity and mortality.     

The effect of high dose atorvastatin therapy on lipids and lipoprotein subfractions in overweight patients with type 2 diabetes

Few data are available on the effects of high dose statin therapy on lipoprotein subfractions in type 2 diabetes. In a double blind randomised placebo-controlled trial we have studied the effects of 80 mg atorvastatin over 8 weeks on LDL, VLDL and HDL subfractions in 40 overweight type 2 diabetes patients. VLDL and LDL subfractions were prepared by density gradient ultracentrifugation. Triglycerides, cholesterol, total protein and phospholipids were measured and mass of subfractions calculated. HDL subfractions were prepared by precipitation. Atorvastatin 80 mg produced significant falls in LDL subfractions (LDL(1) 66.2 mg/dl:36.6 mg/dl, LDL(2) 118:56.6 mg/dl, LDL(3) 36.9:19.9 mg/dl all P < 0.01 relative to placebo) and VLDL subfractions (VLDL(1) 55:22.1 mg/dl, VLDL(2) 40.1:19.1 mg/dl, VLDL(3) 52.6:30 mg/dl all P < 0.01 relative to placebo). There was no change in the proportion of LDL present as LDL(3). There was a reduction in the proportion of VLDL as VLDL(1) and a reciprocal increase in the proportion as VLDL(3). Changes in VLDL subfractions were associated with changes in lipid composition, particularly a reduction in cholesterol ester and a reduction in the cholesterol ester/triglyceride ratio. Effects on HDL subfractions were largely neutral. High dose atorvastatin produces favourable effects on lipoprotein subfractions in type 2 diabetes which may enhance antiatherogenic potential.     

Cellular cholesterol efflux to plasma from moderately hypercholesterolaemic type 1 diabetic patients is enhanced, and is unaffected by simvastatin treatment

Aim/hypothesis Cellular cholesterol efflux to plasma is important in reverse cholesterol transport and may be affected by simvastatin in type 1 diabetes mellitus.Methods In 14 moderately hypercholesterolaemic type 1 diabetic and 13 healthy men we determined plasma (apo)lipoproteins, pre- HDL formation, cholesteryl ester transfer protein (CETP) activity, phospholipid transfer protein (PLTP) activity, cholesterol esterification, cholesteryl ester transfer and the capacity of plasma to induce cholesterol efflux out of Fu5AH cells and fibroblasts. After diet run-in, diabetic patients were randomly treated with simvastatin 10, 20, 40 mg and placebo, once daily each, for 6 weeks in a double-blind crossover design.Results Plasma very low density lipid protein (VLDL)+LDL cholesterol, LDL cholesterol, HDL phospholipids, apolipoprotein (apo) A-I, apo B, CETP activity, PLTP activity, cholesterol esterification, cholesteryl ester transfer and the capacity of plasma to induce cholesterol efflux from Fu5AH cells and fibroblasts were higher in diabetic patients. Pre- HDL formation was unaltered. Simvastatin treatment decreased VLDL+LDL cholesterol, LDL cholesterol, triglycerides and apo B, CETP activity, cholesterol esterification and cholesteryl ester transfer. HDL cholesterol increased and its change was correlated with the change in cholesteryl ester transfer. The ability to promote cholesterol efflux from Fu5AH cells and fibroblasts did not change after simvastatin.Conclusions/interpretation The capacity of plasma from moderately hypercholesterolaemic type 1 diabetic patients to induce cholesterol efflux out of Fu5AH cells and fibroblasts is enhanced, probably due to higher apo A-I, HDL phospholipids and PLTP activity. Simvastatin increases HDL cholesterol in type 1 diabetic patients via lowering of plasma cholesteryl ester transfer. The HDL changes after simvastatin do not increase cellular cholesterol efflux further.