Changes In Lipoprotein Concentrations Research Articles

Effect of olezarsen targeting APOC-III on lipoprotein size and particle number measured by NMR in patients with hypertriglyceridemia

Olezarsen is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apolipoprotein C-III (apoC-III) and triglyceride-rich lipoproteins (TRLs). To define the effect of olezarsen on NMR-derived lipoprotein particle size and concentration. Patients (n=114) with or at risk for atherosclerotic cardiovascular disease and fasting triglycerides ≥200 and <500 mg/dL received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. NMR LipoProfile® analysis was performed in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months. A dose-dependent relationship was generally noted with increasing cumulative doses of olezarsen in TRL particle (TRLP), LDL particle (LDL-P) and HDL (HDL-P) particle concentrations. In the 50 mg every 4 weeks dose, compared to placebo, olezarsen resulted in a significant reduction in total TRL-P (51%, P<0.0001) with largest reductions in large-size (68%, P<0.0001) and medium-size (63%, P<0.0001) TRL-P. Total LDL-P concentration was not changed, but large LDL-P increased by 186% (p=0.0034), and small LDL-P decreased by 39% (p=0.0713). Total HDL-P concentration increased by 15% (P=0.0006), driven primarily by a 32% increase in small HDL subspecies (diameters <8.3 nm) (P=0.0008). Olezarsen results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDL-P. These findings suggest that apoC-III inhibition improves the overall atherogenic risk profile.

Abstract 11174: Effect of APOCIII-L Rx on Lipoprotein Size and Particle Numbers Measured by NMR in Patients with Hypertriglyceridemia: Results of the AKCEA-APOCIII-L Rx Trial

Background: APOCIII-L Rx is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apoC-III and triglyceride-rich lipoproteins (TRLs). We examined the effect of APOCIII-L Rx on a variety of lipoprotein fractions measured by nuclear magnetic resonance (NMR) spectroscopy. Methods: The AKCEA-APOCIII-L Rx trial was a dose-ranging study in 114 patients with, or at risk for, ASCVD and fasting serum triglycerides 200-500 mg/dL. Patients (n=114) received AKCEA-APOCIII-L Rx (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. Comprehensive NMR LipoProfile ® analysis was performed by LipoScience/LabCorp in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months. Results: Results are reported as change from baseline to PAT for the 50 mg every 4 weeks dose versus placebo. APOCIII-L Rx resulted in a significant reduction in total TRL particle (TRLP) concentration by 51% (P&lt;0.0001) with largest reductions in large-size (by 68%, P&lt;0.0001) and medium-size (by 63%, P&lt;0.0001) TRLPs. Total LDL particle (LDLP) concentration was not changed, small LDLP numerically decreased by 39% (P= 0.0713) while medium LDLP increased by 187% (P=0.0119), accompanied by an increase in average LDL size by xx 2% (p=0.0039xx). Total HDL particle (HDLP) concentration increased by 15% (P=0.0006), represented primarily by an increase in small HDL subspecies (particle diameters &lt;8.3 mm) of 32% (P=0.0008). Lower cumulative doses of APOCIII-L Rx generally reflected a dose-dependent relationship in the above parameters. Conclusion: APOCIII-L Rx results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDLP. These findings suggest an improvement in overall atherogenic risk profile.

Postprandial triglyceridaemia is modulated by insulin resistance but not by grade of obesity in abdominal and morbid obese subjects.

Obesity is associated with high cardiovascular risk. Postprandial lipidaemia has been associated with cardiovascular disease risk. Our aim was to identify whether anthropometric parameters, insulin resistance (IR) and/or fasting plasma triglycerides may determine postprandial changes in lipoprotein concentrations in abdominal and morbid obese subjects. We have studied 20 non-diabetic, normolipidaemic subjects with abdominal obesity, 20 morbid obese subjects and 20 healthy individuals, that have similar age and gender. In all of them a standardised oral fat load test (OFLT) with unsaturated fat was performed. During the OFLT, the postprandial triglycerides response was significantly higher in subjects with abdominal obesity compared with morbid obese subjects (4hours triglycerides pick value and AUC of triglycerides). Both obese groups showed significantly higher postprandial triglycerides response compared with healthy subjects. Dividing the obesity group according to the presence of IR, we found that IR was an important factor related with postprandial lipaemia but not BMI or waist circumference. In addition, postprandial glycaemia and insulinaemia significantly decreased in all studied subjects, being the highest decrease in morbid obese subjects and in subjects with IR. Postprandial triglyceridaemia significantly correlated with IR parameters and not with anthropometric parameters in AO and MO subjects. In subjects with AO and MO, postprandial triglycerides values are higher than healthy individuals and independently predicted by fasting IR parameters. Furthermore, unsaturated fat improved IR state.

Hemodilution is not the only reason of difference: Comparison of fasting and non-fasting lipoproteins in paired samples

IntroductionLow-density lipoprotein cholesterol (LDL) is an important risk factor for cardiovascular disease (CVD) and generally measured after 8–12 h fasting. However, some recent studies have pointed that non-fasting lipoproteins, especially LDL concentrations, are better indicators for demonstrating CVD risk and atherosclerosis. They asserted that nutrition is a negligible factor on changes in lipoprotein concentrations and claimed this difference as a result of hemodilution effect, caused from fluid intake and can be eliminated by applying some adjustments. We aimed to compare the fasting and non-fasting LDL values of the same individuals and discuss whether non-fasting and fasting LDL results can be used in place of each other, directly or after applying hemodilution correction models. Material and methodsFasting and non-fasting blood samples of 248 apparently healthy participants were collected. Lipid panel tests, albumin and hemoglobin levels were studied in each sample. Results were evaluated in seven different models which were recommended to correct the hemodilution effect on fasting and non-fasting lipid concentrations of the same individual. Concordance of fasting and non-fasting risk group of the individual were calculated according to the National Cholesterol Education Program classification. ResultsFasting and non-fasting LDL and non-high density lipoprotein cholesterol (non-HDL) concentrations were significantly different in every model (p < 0.001). Concordance results of fasting and non-fasting LDL and non-HDL risk groups were 63.8% and 77.9% respectively. ConclusionsOur results demonstrated that fasting and non-fasting LDL and non-HDL concentrations could not be used in place of each other even when the results were adjusted for elimination of the hemodilution effect.

Trans fatty acids and cardiovascular health: research completed?

This review asks the question if further research on trans fatty acids and cardiovascular health is needed. We therefore review the evidence from human studies on trans fatty acids and cardiovascular health, and provide a quantitative review of effects of trans fatty acid intake on lipoproteins. The results show that the effect of industrially produced trans fatty acids on heart health seen in observational studies is larger than predicted from changes in lipoprotein concentrations. There is debate on the effect of ruminant trans fatty acids and cardiovascular disease. Of special interest is conjugated linoleic acid (CLA), which is produced industrially for sale as supplements. Observational studies do not show higher risks of cardiovascular disease with higher intakes of ruminant trans fatty acids. However, CLA, industrial and ruminant trans fatty acids all raise plasma low-density lipoprotein and the total to high-density lipoprotein ratio. Gram for gram, all trans fatty acids have largely the same effect on blood lipoproteins. In conclusion, the detrimental effects of industrial trans fatty acids on heart health are beyond dispute. The exact size of effect will remain hard to determine. Further research is warranted on the effects of ruminant trans fatty acids and CLA on cardiovascular disease and its risk factors.

Low-Intensity Exercise Exerts Beneficial Effects on Plasma Lipids via PPARγ

An important mechanism by which physical activity reduces the risk of cardiovascular disease is through regulating plasma lipids. We investigated whether low-intensity exercise modulates lipid metabolism and the transcription factors peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor alpha (LXRalpha) responsible for controlling reverse cholesterol transport (RCT). Thirty-four sedentary adults, mean age 45.6 +/- 11.1 yr, participated in an 8-wk low-intensity exercise program consisting of walking 10,000 steps, three times a week. Subjects were randomly allocated to either an exercise group or a sedentary control group, and serum lipid or lipoprotein concentrations were determined. Compared with controls, there was a significant decrease in total cholesterol (preexercise, 5.73 +/- 1.39 mmol x L; postexercise, 5.32 +/- 1.28 mmol x L) and a significant increase in HDL (preexercise, 1.46 +/- 0.47 mmol x L; postexercise, 1.56 +/- 0.50 mmol x L) after the exercise program. There was a significant increase in serum oxidized LDL (oxLDL) concentrations in the exercise group before and after exercise (0 wk, 554 +/- 107 ng x mL; 4 wk, 698 +/- 134 ng x mL; 8 wk, 588 +/- 145 ng x mL). A significant increase in leukocyte mRNA expression for PPARgamma (4 wk, 1.8 +/- 0.9-fold; 8 wk, 4.3 +/- 1.9-fold) was observed, which was reinforced by increased PPARgamma DNA-binding activity postexercise (preexercise, 0.22 +/- 0.09 OD units; postexercise, 1.13 +/- 0.29 OD units). A significant increase in gene expression was observed for the oxLDL scavenger receptor CD36 (4 wk, 3.8 +/- 0.6-fold; 8 wk, 2.7 +/- 0.5-fold) and LXRalpha (8 wk, 3.5 +/- 0.8-fold). Two LXRalpha-regulated genes involved in RCT, namely, ATP-binding cassette transporters A1 and GI (ABCA1 and ABCG1, respectively), were significantly up-regulated postexercise (8 wk: ABCA1, 3.46 +/- 0.56-fold; ABCG1, 3.06 +/- 0.47-fold). We propose that the net effect of these changes may be to increase oxLDL uptake, to stimulate RCT, and thus to promote clearance of proatherogenic lipids from the vasculature, ultimately contributing to the cardiovascular benefits of low-intensity aerobic exercise.

Efficacy of controlled-release niacin in treatment of metabolic syndrome: Correlation to surrogate markers of atherosclerosis, vascular reactivity, and inflammation

The mechanisms that link metabolic syndrome to development of atherosclerosis are largely unknown. There is increasing evidence for the role of adipokines in this process. Niacin would appear to be a logical choice in combating the atherogenic dyslipidemia seen in metabolic syndrome, as it remains the most effective agent in raising high-density lipoprotein cholesterol, and also reduces triglycerides. We hypothesized that statin-intolerant patients with insulin resistance would respond to controlled-release niacin with a rise in plasma adiponectin levels. Fifty patients with the metabolic syndrome (National Cholesterol Education Program/Adult Treatment Panel III criteria) were randomized to either once-daily controlled-release niacin (1000 mg/day) or placebo. Measurements at baseline and after 52 weeks of treatment were made of the carotid intimal media thickness, flow-mediated dilation of the brachial artery, and blood plasma adiponectin levels. These measures were compared to changes in lipoprotein concentrations in plasma. Changes in high-density lipoprotein cholesterol correlated significantly to changes in flow-mediated vasodilation and carotid artery intima-media thickness, and there was a trend toward correlation with plasma adiponectin levels. There was a significant difference in mean serum levels of adiponectin after the treatment period between placebo and niacin groups (16.3 ± 1.7 and 17.7 ± 1.9 mg/dL, respectively) (P = 0.022). Treatment with controlled-release niacin for 52 weeks results in sustained improvements in adiponectin levels compared to placebo in patients with metabolic syndrome. No adverse effects of niacin on glycemic control were found.

Effects of rosuvastatin on postprandial leukocytes in mildly hyperlipidemic patients with premature coronary sclerosis

We investigated whether pro-inflammatory aspects of the postprandial phase can be modulated by rosuvastatin in premature coronary artery disease (CAD) patients. Herefore standardized 8 h oral fat loading tests were performed off-treatment and after rosuvastatin 40 mg/d in 20 male CAD patients (50 ± 4 years). The expression of leukocyte activation markers CD11a, CD11b, CD62L and CD66b was studied using flowcytometry. Migration of isolated neutrophils towards chemoattractants was determined in a fluorescence-based assay. Rosuvastatin did not affect baseline leukocyte counts nor the postprandial neutrophil increment (maximum mean increase +10% pre- and +14% post-treatment, P < 0.01 for each). Rosuvastatin reduced baseline platelets (from 266 ± 78 to 225 ± 74 × 10 9 cells/L, P < 0.001) and blunted the postprandial platelet count change (maximum mean increase +6%, P = 0.01, and 0%, respectively). The baseline expression of CD11a, CD11b and CD62L increased on most types of leukocytes by rosuvastatin, whereas the postprandial responses were unaffected. Pretreatment, postprandial neutrophil migration increased dose-dependently, but there were no postprandial changes after rosuvastatin. The latter effect was unrelated to changes in lipoprotein concentrations. In conclusion, in CAD patients postprandial pro-inflammatory and pro-coagulant changes can be modified by rosuvastatin. These apparently lipid-lowering independent effects may render protection against atherosclerosis.

Acute changes in serum lipids and lipoprotein subclasses in triathletes as assessed by proton nuclear magnetic resonance spectroscopy.

Exercise is associated with changes in lipids that may protect against coronary heart disease (CHD). In this study of 28 triathletes, we analyzed acute changes in serum lipid and lipoprotein concentrations after completion of the 1995 World Championship Hawaii Ironman Triathlon. With standard laboratory assays, we demonstrate significant decreases in total cholesterol, VLDL cholesterol, ApoB100, and Lp(a). Total HDL cholesterol increased significantly immediately after the race. With a novel proton NMR spectroscopy assay, we demonstrate that smaller diameter LDL particles, corresponding to small, dense LDL, declined by 62%. Moreover, larger HDL subclasses, whose levels are inversely associated with CHD, increased significantly by 11%. Smaller HDL subclasses, which have been directly associated with CHD in some studies, acutely decreased by 16%. Therefore, exercise not only acutely induces changes in lipoprotein concentrations among the standard species in a manner that favorably affects CHD risk, but also induces favorable changes in specific lipoprotein subclass size distribution that also may alter CHD risk independently of the total lipoprotein serum concentration.

Pregnancy in a patient with homozygous familial hypercholesterolemia undergoing low-density lipoprotein apheresis by dextran sulfate adsorption

Pregnancy and delivery in homozygous familial hypercholesterolemic (HFH) patients is extremely rare. We describe the case of a woman with HFH treated with low-density lipoprotein (LDL) apheresis by dextran sulfate adsorption who became pregnant and reached delivery uneventfully. LDL apheresis was performed biweekly, and lipoprotein analyses in pre-apheresis samples showed progressive increases in triglyceride, total cholesterol, LDL cholesterol, and apolipoprotein (apo) B plasma concentrations. The fractional catabolic rate (FCR) for LDL cholesterol, as estimated by the first-order disappearance constants ( k values) of the recovery of LDL cholesterol concentration to basal values after each apheresis session, increased more than threefold from week-24 to week-4 (labor is considered as time 0). After delivery, basal values were recovered, but normalization was slower for LDL cholesterol than for the other lipidic parameters. High-density lipoprotein (HDL) showed a different pattern: HDL 3 remained stable throughout gestation, whereas HDL 2 cholesterol and apo A-I had a maximum at midgestation, then declined, and finally increased again at late gestation. With the exception of this latter increase of HDL 2, all the other changes in lipoprotein concentrations during pregnancy and postpartum were similar to those found in healthy women. Thus, LDL apheresis does not interfere with physiologic adaptations of lipoprotein metabolism during pregnancy in HFH patients.

Low dose continuously infused growth hormone results in increased lipoprotein(a) and decreased low density lipoprotein cholesterol concentrations in middle-aged men.

Animal studies have shown that slight increases in basal GH concentrations may result in changes in lipoprotein metabolism. Such changes in GH secretion have been observed in physiological and pathophysiological states such as fasting, uncontrolled diabetes and during oestrogen treatment. The aim of this study was to investigate the possible effects of increases in basal plasma GH concentrations on lipoprotein concentrations. Recombinant human growth hormone (rhGH) was given as a continuous subcutaneous infusion in a low dose (0.02 U/kg/day) in an open study. Eight middle-aged (42-59 years) overweight (body mass index: 26.1-33.8 kg/m2) but otherwise healthy men were studied over a period of 14 days. Blood samples were obtained after an over-night fast before and after 2, 7 and 14 days of treatment. Plasma and serum were separated and used for subsequent measurements of hormone and lipoprotein concentrations. On days 0, 7 and 14 of treatment, post-heparin plasma was also obtained for determinations of plasma lipoprotein lipase and hepatic lipase activities. In addition, a hyperinsulinaemic euglycaemic glucose clamp was performed on days 0 and 13 of the study. Fat biopsies from abdominal and gluteal fat depots were obtained for measurement of lipoprotein lipase activities on days 0 and 14 of the study. Serum GH concentrations increased to a steady level of 2-4 mU/l during treatment. Serum insulin-like growth factor-I (IGF-I) concentrations increased throughout the treatment period to twice the pretreatment levels. Plasma insulin and blood glucose concentrations increased on day 2 of treatment. After 7 and 14 days of treatment blood glucose concentrations were not different from pretreatment levels, but plasma insulin concentrations were still elevated. Serum cholesterol and low density lipoprotein (LDL) cholesterol concentrations had decreased after 7 and 14 days of treatment. High density lipoprotein (HDL) cholesterol concentrations were not affected, but very low density lipoprotein (VLDL) cholesterol and triglyceride concentrations increased transiently at day 2 of treatment. Serum apolipoprotein (apo) A-I, apoB and apoE concentrations were not significantly affected. Serum lipoprotein(a) concentrations had increased by days 7 and 14 to 147 and 142% of pretreatment concentrations, respectively. Lipoprotein lipase and hepatic lipase activities in post-heparin plasma, as well as abdominal and gluteal adipose tissue lipoprotein lipase activities, were not affected. There was no significant change in glucose disposal rate estimated from the glucose clamp studies. A low dose infusion of GH results in marked changes in lipoprotein concentrations with a transient increase in VLDL cholesterol and thereafter in a decrease in LDL cholesterol. In addition, this low dose of GH resulted in marked increases in lipoprotein(a) concentrations. The observed effects of GH may partly involve changes in IGF-I and insulin secretion.

Hypocholesterolemic effects of a dietary fiber supplement

The cholesterol-lowering effects of a fiber supplement were evaluated in patients with mild to moderate hypercholesterolemia. After a 9-wk diet stabilization period, patients were randomly assigned to treatment with 10 or 20 g/d of the fiber supplement or with a matching placebo. Among patients who completed the 15-wk treatment period, total cholesterol, LDL cholesterol, and the ratio of LDL to HDL (LDL/HDL) were significantly reduced (P < 0.05) for the 10- (n = 40) and 20-g/d (n = 39) groups compared with the placebo group (n = 48). In the placebo group and 10- and 20-g/d groups, the percent changes in total cholesterol were 0.4%, -5.8%, and -4.9%, in LDL cholesterol were -0.4%, -8.1%, and -7.3%, and in LDL/HDL were 1.0%, -5.6%, and -8.7%, respectively. The fiber supplement had no significant effects (P > 0.05) on HDL cholesterol or triglycerides. The changes in lipoprotein concentrations could not be attributed to changes in diet or body weight because there were no significant changes in these variables during the 15-wk treatment period.

The effect of nicotinic acid and acipimox on lipoprotein(a) concentration and turnover

This study examines the effect of nicotinic acid (1 g t.d.s.) on serum Lp(a) concentration in a group of patients with type II hyperlipidaemia selected on the basis of a plasma Lp(a) concentration greater than 30 mg/dl. Reductions in total cholesterol, triglyceride, LDL-cholesterol and Lp(a) were 16.3%, 25.5%, 23.7% and 36.4%, respectively, with an increase in HDL cholesterol of 37.3%. The reduction in Lp(a) concentration did not correlate with any other lipoprotein changes. In order to establish the mechanism of the fall in Lp(a) concentration, in vivo turnover of autologous Lp(a) was studied in three subjects before and whilst taking nicotinic acid. The fractional catabolic rate in Lp(a) was unaltered in the subjects on therapy, indicating that nicotinic acid did not increase catabolism of Lp(a) but decreased the synthetic rate. Since nicotinic acid was poorly tolerated we examined the effect of acipimox, an analogue of nicotinic acid on lipoproteins using a placebo controlled double-blind crossover design in a group of hyperlipidaemic patients again selected with plasma Lp(a) concentration greater than 30 mg/dl. Acipimox was better tolerated than nicotinic acid but the percentage changes in lipoprotein concentrations were smaller.

The role of lipids and antioxidative factors for development of atherosclerosis: The Probucol Quantitative Regression Swedish Trial (PQRST)

The effect of probucol on the development of atherosclerosis is being investigated in the Probucol Quantitative Regression Swedish Trial (PQRST). Hypercholesterolemic patients are randomized to receive either probucol 0.5 g twice daily or placebo in a double-blind manner, in combination with dietary therapy and cholestyramine 8–16 g daily for a 3-year period. The primary endpoint of the trial is the change in atheroma volume, assessed by annual quantitative angiography involving 20-cm segments of the femoral artery. Data from the open diet and prerandomization phase indicate that probucol added to dietary intervention plus cholestyramine produced highly significant reductions in total (−17%), low-density lipoprotein (LDL; −10%), and high-density lipoprotein (−30%) cholesterol. From a subpopulation, LDL levels were isolated during different stages of the prerandomization phase. LDL was exposed to the oxidant Cu 2+ and binding to fibroblasts as well as degradation by macrophages was measured. The generation of thiobarbituric acid-reactive substances (TBARS) was also measured. Probucol prevented degradation of copper-exposed LDL by macrophages and also reduced the formation of TBARS, indicating that probucol protected LDL from oxidation. After the trial concludes in December 1992, statistical models will be used to investigate how much of the change in atherosclerosis is explained by changes in lipoprotein concentrations and how much is explained by probucol's antioxidative effects. Thus, other metabolic factors such as dietary intake and circulating levels of lipid soluble vitamins and fatty acids that may modify the possible antioxidative effects of probucol are also measured and will be related to change in atherosclerosis.

Acute and delayed effects of prolonged exercise on serum lipoproteins. I. Composition and distribution of high density lipoprotein subfractions.

To investigate the effects of a single period of prolonged exercise on lipoprotein concentration and composition, the serum of 13 healthy, endurance-trained men was examined before and after (1 h, 20 h) a field test [running time, 130 (SD 7.4) min]. We found changes in composition of all of the lipoprotein fractions isolated. In detail, all very low density lipoprotein particle components were reduced after exercise; the most pronounced changes found were in the concentrations of phospholipids (PL) and triglycerides (TG) (PL, before vs 20 h after, P < 0.01; TG, before vs 20 h after, P < 0.01). The serum high density lipoprotein (HDL)-cholesterol mass was unchanged after exercise, but both HDL subfractions showed changes in composition. In HDL3 the relative amounts of cholesterol increased (unesterified free cholesterol; FC) before vs 20 h after, P < 0.05; cholesterylester (CE), before vs 20 h after, P < 0.01) and TG and PL decreased (TG and PL, before vs 20 h after, P < 0.05). The HDL2 particles became enriched in the relative amount of CE (before vs 20 h after, P < 0.01) and lost TG after exercise (before vs 20 h after, P < 0.01). The observation that all the changes in lipoprotein concentration and composition reached their maximal differences compared to the pre-exercise values 20 h afterwards would support the assumption that circulating lipoproteins play an important role in the regeneration period, refilling the intramuscular triglyceride stores.

Effect of interleukin-1 alpha on lipoprotein lipids in cynomolgus monkeys: Comparison to tumor necrosis factor

Acute inflammation is associated with changes in lipoprotein metabolism. Cytokines are thought to mediate the metabolic effects of the inflammatory process. This study was undertaken to compare the effects of interleukin-1α (IL-1α) to tumor necrosis factor (TNF) on lipoprotein metabolism in non-human primates. Recombinant human IL-1α (100 μg/kg), TNFα (20 μg/kg) and lipopolysaccharide (20 μg/kg) were injected into cynomolgus monkeys. Lipoprotein concentrations, plasma activities of post-heparin lipase (PHLA) and lecithin:cholesterol acyltransferase (LCAT) were measured prior to and 24 and 48 h after, injection. All three injectates caused afebrile response in the animals. Interleukin-1α had no effect on plasma lipoprotein concentrations, composition of lipoproteins or enzyme activity. In contrast, injection of TNF caused significant changes in lipoprotein concentrations. There was a 38% increase in plasma triacylglycerol and 30% decrease in plasma cholesterol at 48 h after injection. Concentrations of apolipoproteins A-I and B were decreased 20% and 44%, respectively, at 48 h. Compositional analyses of lipoprotein particles after TNF injection showed that both the LDL and HDL particles had decreased content of cholesterol ester and increased triacylglycerol after injection, and plasma activities of PHLA and LCAT were decreased. These changes were qualitatively similar to those seen after LPS injection. These data suggest that, unlike TNF, IL-1α is not an important mediator of the inflammatory process on lipoprotein metabolism in cynomolgus monkeys.

Changes in Lipoprotein Concentrations during the Development of Noninsulin-Dependent Diabetes Mellitus in Obese Rhesus Monkeys (Macaca mulatta)*

Abnormalities in plasma lipoprotein concentrations commonly found in subjects with noninsulin-dependent diabetes may be related to insulin resistance, hyperinsulinemia, hyperglycemia, or other metabolic defects. The middle-aged obese rhesus monkey is an animal model in which these defects can be separated in time during the development of diabetes. It is, therefore, a model system for examining the sequence of metabolic changes which occur before and after the onset of diabetes. This sequence of changes was used in the present study to determine if lipoprotein changes occur in association with the development of diabetes in the rhesus monkey. Increases in plasma triglyceride, very low density lipoprotein (VLDL) triglyceride, and VLDL cholesterol, and decreases in high density lipoprotein cholesterol were observed across previously identified groups ranging from normal to diabetic. Plasma triglycerides increased from 0.54 +/- 0.09 (normal) to 1.27 +/- 0.50, 1.93 +/- 0.79, and 4.28 +/- 2.24 in three intermediate groups with progressive hyperinsulinemia and insulin resistance, to 7.59 +/- 2.73 mmol/L in the diabetic monkeys. Increases in VLDL triglyceride and VLDL cholesterol paralleled the plasma triglyceride increases. High density lipoprotein cholesterol decreased across the groups from 2.33 +/- 0.16 (normal) to 1.72 +/- 0.20, 1.17 +/- 0.13, and 1.09 +/- 0.20 mmol/L in the intermediate groups, and was lowest in the diabetic monkeys, 1.00 +/- 0.21. The obese rhesus monkey can therefore be used to study lipoprotein abnormalities as they occur both before and in noninsulin-dependent diabetes.

Effects of ω-3 Fish Oils on Plasma Lipids, Lipoprotein Composition, and Postheparin Lipoprotein Lipase in Women With IDDM

Because the apparent reduction in cardiovascular risk noted in nondiabetic populations that ingest diets rich in marine lipids containing omega-3 fatty acids is believed to result in part from their capacity to modify the composition and physicochemical behavior of lipoproteins, we sought to determine whether dietary supplementation with marine lipids might favorably affect lipoprotein composition in insulin-dependent diabetes mellitus (IDDM). Eight normolipidemic IDDM women (mean +/- SD age 29.8 +/- 4.7 yr) were studied before and 3 mo after receiving a marine-lipid concentrate (Super-EPA) containing 6 g omega-3 fatty acids and a total of 12 mg of cholesterol daily. Weight, insulin requirements, and glycosylated hemoglobin remained stable. After treatment, mean +/- SD plasma triglyceride (TG) levels fell (before, 81.7 +/- 22 mg/dl; after, 69.19 +/- 17; P less than 0.025). High-density lipoprotein2 (HDL2) cholesterol (before, 10.98 +/- 5.45 mg/dl; after, 18.43 +/- 7.93; P less than 0.01), its major apolipoprotein A-I (apoAI), and the major phospholipids (sphingomyelin and lecithin) all rose significantly. ApoB and plasma and low-density lipoprotein cholesterol levels and HDL3 composition were unchanged. Postheparin hepatic and lipoprotein lipase activities were unaffected by marine lipids. These data indicate that women with IDDM experience apparently beneficial effects on TG and HDL2 from dietary supplementation with omega-3 fatty acids administered in a low-cholesterol-containing oil without adversely affecting overall diabetes management. If these changes in lipoprotein concentration and composition prove to have antiatherogenic consequences and are free of long-term toxicity, these agents may have a role in the therapy of IDDM patients.

Hypolipidemic 2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-ones. Structure-activity relationships of a novel series of high-density lipoprotein elevators.

The preparation and plasma lipid altering characteristics of a series of 4H-3,1-benzoxazin-4-ones are described. Hypocholesterolemic, hypotriglyceridemic, and high-density-lipoprotein elevating properties are found for derivatives bearing a 4-(1,1-dimethylethyl)phenyl group at the 2-position, and this activity is displayed in both hypercholesterolemic and in normolipidemic rats when the ring system is substituted at position 6 with hydrogen, methyl, chloro, or iodo groups, and is optimal when the 6-position is substituted by a bromine atom. Evidence is presented suggesting that a metabolite or degradation product is responsible for the changes in lipoprotein concentration observed with active molecules of this type. Synthesis of anticipated degradation products of the active molecules gave products displaying the expected in vivo activity, but no improvement in the narrow therapeutic margin of the best compound, 6-bromo-2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-one, was obtained.

The effects of conjugated equine estrogens plus cyclical dydrogesterone on serum lipoproteins and apoproteins in postmenopausal women.

Serum lipoprotein and apoprotein concentrations were monitored for 24 weeks in 26 postmenopausal women treated with conjugated equine estrogens (0.625 mg/day) with the addition of dydrogesterone (10 mg/day) for the last 12 days of each 28 day cycle. The women had had no previous hormone replacement therapy. The estrogen plus dydrogesterone regimen caused significant (P less than 0.05) increases in triacylglycerol and HDL cholesterol concentrations. Both HDL2 and HDL3 cholesterol were increased. There were no other significant changes in lipoprotein concentrations. Both apoprotein AI and apoprotein AII concentrations increased significantly (P less than 0.05) over the study period. The ratios of apoprotein AI to apoprotein AII, apoprotein AI to HDL cholesterol and apoprotein AII to HDL cholesterol did not change. At the doses employed in this study, the use of dydrogesterone as a progestogen alters the effects of conjugated equine estrogens on lipoproteins and reinforces the view that the effects of a combined HRT regimen cannot be predicted from a consideration of the effects of the individual components.