Effects of insulin on hypercholesterolemia in the streptozotocin-induced diabetic rats fed a high cholesterol diet

The effect of dietary cholesterol (Ch) on plasma lipoprotein and apolipoproteins (apo) in diabetic rats was investigated. Ch-fed diabetic rats were severely hypercholesterolemic and hypertriglyceridemic. They had higher concentrations of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL). Concentration of high density lipoprotein (HDL) was decreased. beta-VLDL increased predominantly in Ch-fed diabetic rats, whereas IDL increased in the Ch and propylthiouracil-fed control rats. According to sodium dodecyl sulfate polyacrylamide gel electrophoresis, VLDL and IDL from Ch-fed diabetic rats were unusual in that they contained more apo E, A-I and A-IV. Concentrations of plasma apo A-I and apo E were measured by radioimmunoassay. The diabetic rats fed a labo chow showed a significantly lower concentration of plasma apo E than control rats. Plasma apo E was extremely higher in the diabetic rats fed a cholesterol diet. Plasma apo A-I was significantly increased in the diabetic rats fed a labo chow and those fed a cholesterol. Insulin treatment significantly decreased the concentrations of VLDL, IDL and LDL and plasma concentration and distribution of apolipoproteins in lipoprotein subfractions changed toward normal. However, decreased HDL in the Ch-fed diabetic rats was not recovered by insulin treatment.     

Differential effect of fenofibrate and atorvastatin on in vivo kinetics of apolipoproteins B-100 and B-48 in subjects with type 2 diabetes mellitus with marked hypertriglyceridemia

The specific impact of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and fibrates on the in vivo metabolism of apolipoprotein (apo) B has not been systematically investigated in patients with type 2 diabetes mellitus with high plasma triglyceride (TG) levels. Therefore, the objective of this 2-group parallel study was to examine the differential effects of a 6-week treatment with atorvastatin or fenofibrate on in vivo kinetics of apo B-48 and B-100 in men with type 2 diabetes mellitus with marked hypertriglyceridemia. Apolipoprotein B kinetics were assessed at baseline and at the end of the intervention using a primed constant infusion of [5,5,5-D(3)]-l-leucine for 12 hours in the fed state. Fenofibrate significantly decreased plasma TG levels with no significant change in plasma low-density lipoprotein cholesterol (LDL-C) and apo B levels. On the other hand, atorvastatin significantly reduced plasma levels of TG, LDL-C, and apo B. After treatment with fenofibrate, very low-density lipoprotein (VLDL) apo B-100 pool size (PS) was decreased because of an increase in the fractional catabolic rate (FCR) of VLDL apo B-100. No significant change was observed in the kinetics of LDL apo B-100. Moreover, fenofibrate significantly decreased TG-rich lipoprotein (TRL) apo B-48 PS because of a significant increase in TRL apo B-48 FCR. After treatment with atorvastatin, VLDL and IDL apo B-100 PSs were significantly decreased because of significant elevations in the FCR of these subfractions. Low-density lipoprotein apo B-100 PS was significantly lowered because of a tendency toward decreased LDL apo B-100 production rate (PR). Finally, atorvastatin reduced TRL apo B-48 PS because of a significant decrease in the PR of this subfraction. These results indicate that fenofibrate increases TRL apo B-48 as well as VLDL apo B-100 clearance in men with type 2 diabetes mellitus with marked hypertriglyceridemia, whereas atorvastatin increases both VLDL and IDL apo B-100 clearance and decreases TRL apo B-48 and LDL apo B-100 PR.     

Pravastatin therapy in primary moderate hypercholesterolaemia: changes in metabolism of apolipoprotein B-containing lipoproteins

This study examined the actions of pravastatin on the metabolism of apolipoprotein B (apo B) in very low-, intermediate-, and low-density lipoproteins (VLDL, IDL, and LDL) in 10 patients with primary moderate hypercholesterolaemia. 131I-VLDL apo B was used as a tracer, and appearance of label was followed into IDL apo B and LDL apo B. Compared to placebo, pravastatin therapy reduced levels of cholesterol in total plasma. LDL, VLDL, and IDL cholesterol by 25%, 29%, 31%, and 47%, respectively. Pravastatin treatment also significantly decreased concentrations of apo B in LDL, IDL, and VLDL. The drug significantly reduced the mean production rate for VLDL apo B by 40%, and decreased production rates for LDL apo B in eight of 10 patients. In contrast, fractional catabolic rates (FCRs) were not altered significantly in any of the three lipoprotein fractions on pravastatin therapy. Further, pravastatin produced no consistent changes in LDL particle size, composition, or LDL subclass pattern. Thus pravastatin seemingly reduced input rates for all apo B-containing lipoproteins. Consistent with previous studies, this response was most likely the result of enhanced removal of nascent lipoproteins by increased activity of LDL receptors, although decreased synthesis of apo B in the liver is a possible second action.     

Catabolic defect of triglyceride is associated with abnormal very-low-density lipoprotein in experimental nephrosis

Very-low-density lipoprotein (VLDL)-triglyceride (TG) kinetics were examined in puromycin aminonucleoside-induced nephrotic rats in order to establish the nature of the hypertriglyceridemia associated with this condition. Nephrotic rats had a plasma TG concentration 10-fold higher than the controls. In nephrotic rats TG secretion rate was elevated only 1.2-fold above the controls, suggesting that the catabolism of TG was also impaired. Lipolytic activities were determined in postheparin plasma (PHP) of the control and the nephrotic rats. There were no significant differences in either the activity of lipoprotein lipase (LPL) or hepatic lipase (HL). VLDL-TG was endogenously radiolabeled in donor rats with [2-3H]-glycerol. The half life (T1/2) was then determined by monitoring the clearance of plasma [3H]-VLDL-TG in normal recipient animals. The T1/2 of VLDL-TG from nephrotic rats was twice that of normal rats. The defect in VLDL-TG clearance could be partially rectified by preincubation with high-density lipoprotein (HDL) from normal rats, but not with HDL from nephrotic rats. VLDL from either nephrotic or normal rats were incubated with PHP of normal rats to assess the effectiveness of VLDL-TG as a substrate for PHP. The lipolytic rate for nephrotic VLDL was significantly lower than that for normal VLDL, suggesting that VLDL from nephrotic rats was somewhat resistant to the action of LPL and HL. When VLDL from nephrotic rats was preincubated with HDL from normal rats, the low lipolytic rate of VLDL-TG improved significantly. This was not observed when HDL from nephrotic rats was used for the preincubation. The results suggested that physical and/or chemical change of VLDL particles due to nephrosis results in a catabolic defect of VLDL-TG.     

Effects of atorvastatin on triglyceride-rich lipoproteins, low-density lipoprotein subclass, and C-reactive protein in hemodialysis patients

Dyslipidemia is an important risk factor for cardiovascular disease in patients with chronic renal failure (CRF). We evaluated the safety and efficacy of atorvastatin in patients with dyslipidemia associated with CRF who were undergoing hemodialysis (HD). Thirty-five patients who were receiving HD were given atorvastatin (10 mg/d) for 3 months. Chylomicron (CM), light and dense very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and light and dense low-density lipoprotein (LDL) were separated by ultracentrifugation. Apolipoprotein (apo) B was measured by electroimmunoassay. Mean LDL particle diameter was measured by gradient gel electrophoresis. Atorvastatin therapy reduced LDL-cholesterol (C) by 36% and remnant-like particle (RLP)-C by 58%. Atorvastatin significantly reduced apo B, apo CIII, and apo E in VLDL by 40% to 46% and IDL-apo B by 66%. Atorvastatin also significantly reduced cholesterol in CM, light VLDL, and dense VLDL without consistently affecting triglyceride (TG) in these lipoproteins. Atorvastatin similarly reduced both light and dense LDL-apo B by 38%. LDL particle size in the HD patients significantly increased during atorvastatin treatment from 25.7 +/- 0.4 to 26.2 +/- 0.6 nm. High sensitive C-reactive protein (HS-CRP) was halved by atorvastatin decreasing from 0.08 +/- 0.05 to 0.04 +/- 0.03 mg/dL. Atorvastatin treatment did not affect the creatinine kinase level, and no classical adverse effects were observed during the study. These results suggest that atorvastatin is safe and effective for the management of dyslipidemia in patients with CFR who are receiving HD, which may help to suppress the development of atherosclerosis.     

Changes in the composition of plasma lipoproteins in the chronic uremic rat

The effect of chronic renal failure on the lipid and apolipoprotein concentrations of plasma, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL) was studied in an experimental uremic rat model. Control rats were sham-operated and were divided into adlibitum-fed and pair-fed groups. The rats were studied (after an overnight fast) 32 days after the onset of uremia. The uremic rats had a 4-fold increase in plasma urea nitrogen and creatinine. The pair-fed and ad-lib-fed controls had similar levels of plasma urea nitrogen and lipid profiles. In the uremic rats, plasma triglyceride (TG) levels were increased 3.8-fold due to increased TG in the VLDL, IDL and HDL fractions. Their 2-3-fold increase in plasma free cholesterol (FC), esterified cholesterol (EC) and phospholipids (PL) were due to FC, EC and PL increases in VLDL, IDL, LDL and HDL. Their increase in plasma apo B (x 2.4) and apo E (x 1.5) were due to increases in VLDL, IDL and LDL. Their plasma apo A-I increased 2.4 fold due to increases in the LDL and HDL fractions. Uremic rats also had increases in the FC/PL molar ratio in VLDL, IDL and LDL. In their LDL, the apo B/total cholesterol (TC), apo B/PL and apo B/apo E molar ratios were decreased. In their HDL, the apo E/TC and apo E/PL molar ratios were decreased and the apo A-I/apo E molar ratio was increased. In conclusion, chronic uremia causes both quantitative changes in the levels and qualitative changes in the composition of the plasma lipoprotein particles. These results are compatible with the decreased hepatic lipase activities and impairment of remnant clearance observed in human chronic renal failure.     

Insulin-treated Zucker diabetic fatty rats retain the hypertriglyceridemia associated with obesity

Lipoprotein and apolipoprotein changes were evaluated in 10-week-old Zucker diabetic fatty (ZDF) male rats following 12 weeks of insulin treatment, which normalized blood glucose and maintained weight gaining characteristic of nondiabetic Zucker fatty rats. Compared with untreated ZDF rats (saline-injected), insulin treatment resulted in increased very-low-density lipoprotein (VLDL; d < 1.006 g/mL) and decreased alpha lipoprotein on agarose gel electrophoresis. These findings were consistent with an observed increase in VLDL triglyceride and cholesterol, and decreased high-density lipoprotein (HDL) cholesterol with insulin treatment in isolated lipoproteins. B100 levels were unchanged by insulin treatment, but B48 levels were significantly increased in the VLDL fraction. Insulin treatment depressed apolipoprotein (apo) A-I levels in HDL, but had little effect on total apo E, apo A-IV, or apo C, although apo C was redistributed to the VLDL fraction. These results suggest that insulin treatment of ZDF rats normalizes hyperglycemia and prevents age-related changes in lipoprotein parameters associated with development of insulinopenic diabetes. Insulin therapy in ZDF rats thereby sustains the hyperlipidemic lipoprotein pattern associated with hyperinsulinemia and obesity.     

Catabolism of apoprotein A-1 of HDL in normal and nephrotic rats

High density lipoprotein was isolated from the plasma of control and puromycin aminonucleoside nephrotic rats and labeled with ¹²⁵I. It was injected into control and nephrotic rats and the plasma analyzed after 3 min, 5 hr, and 20 hr. High density lipoprotein was isolated and the specific activity of apo A-I determined following apoprotein separation using SDS-polyacrylamide gel electrophoresis. The distribution of labeled apoproteins was determined in whole plasma by SDS-gel filtration column chromatography and the plasma concentration of apo A-I was calculated from its specific activity and the total plasma apo A-I radioactivity. A 3 min to 5 or 20 hr fractional catabolic rate was calculated. When multiplied by the plasma concentration of apo A-I, an estimate of the absolute catabolic rate was obtained. When injected into normal animals, the high density lipoprotein apo A-I had similar catabolic rates whether derived from control or nephrotic rat plasma, averaging 65 and 48 μg of apoprotein per ml of plasma per hr at 5 or 20 hr, respectively. Labeled HDL was injected into nephrotic rats of varying degrees of severity. The moderately nephrotic rats with plasma cholesterol levels averaging 177 mg/dl had apo A-I levels that were 3.6 times that of controls (1799 ± 195 μg/ml) and 2.4-fold increases in apo A-I catabolic rates (134 ± 28.9 μg/ml plasma/hr). The severely nephrotic rats with cholesterol concentrations averaging 396 mg/dl had apo A-I levels 7.1 times that of the controls (3533 ± 220 μg/ml) while the catabolic rate was 2.7 times the control rate (153 ± 19.5 μg/ml/hr), which was not a significant increase beyond that of the moderately nephrotic group. It was concluded that compositional differences of HDL resulting in an increased proportion of apo A-I, as in nephrotic rat plasma, do not affect apo A-I metabolism. The high levels of apo A-I in the plasma of nephrotic rats is due to increased hepatic synthesis that results in an expansion of the pool size and saturation of catabolic pathways. Small increases in apo A-I synthesis lead to large increases in the plasma concentration, an observation that may be important in the regulation of HDL levels that are known to be correlated with a decreased incidence of atherosclerosis.     

Lipoprotein distribution and composition in the human nephrotic syndrome

Plasma lipoprotein profiles were quantitated in 9 patients with the nephrotic syndrome. Six subjects were studied both during an active proteinuric phase and during a remission phase without proteinuria. During the proteinuric phase, the plasma triglyceride, cholesterol and apo B levels were markedly increased, whereas the HDL cholesterol, apo A-I, and apo A-II concentrations were normal. Analysis of the distribution and composition of the lipoprotein subclasses, separated by isopycnic ultracentrifugation, showed typical patterns characterized by: (1) elevated apo B-rich VLDL and LDL fractions, (2) the presence of a denser LDL subfraction, floating at d 1.053 g/ml, which contained about 35% of LDL cholesterol and apo B and (3) a redistribution among HDL subclasses. The HDL2b (d 1.063-1.100 g/ml) fraction was markedly decreased, while the HDL2a + 3a (d 1.100-1.150 g/ml) and HDL3b + 3c (d 1.150-1.210 g/ml) subclasses were moderately elevated. The decreased cholesterol and apo A-I contents of HDL2b therefore counterbalanced their increase in HDL2a + 3a and HDL3b + 3c, resulting in normal plasma HDL cholesterol and apo A-I concentrations. When reinvestigated during a remission phase without proteinuria, the nephrotic patient's overall lipoprotein distribution and composition were similar to those in healthy controls. The combination of several factors such as the presence of elevated apo B-rich VLDL, IDL and LDL, together with decreased HDL2 cholesterol and HDL2 apo A-I suggests that nephrotic patients are at increased risk for atherosclerosis.     

Sex and hormonal status influence the effects of psyllium on lipoprotein remodeling and composition

We evaluated the influence of sex and hormonal status on the effect of psyllium (PSY) supplementation on parameters of plasma lipoprotein metabolism. Twenty-four men, 23 premenopausal women, and 21 postmenopausal women (PMW) were randomly assigned to a fiber supplement (15 g PSY/d) or a control, provided via cookies, in a crossover design. Plasma lipids, insulin, apoprotein (apo) B, apo CI, apo CIII, and apo E concentrations and the composition and size of low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) particles were measured at the end of each 30-day treatment period. Compared with control, PSY intake decreased plasma LDL cholesterol by an average of 8% (P <.0001) in men and pre- and PMW. There was a fiber-sex/hormonal status interaction on plasma triglycerides (TG) in the response to the intervention. Men had a 17% decrease in TG, while PMW had a 16% increase with PSY (P <.01). Plasma levels of apo C III, apo E, and insulin followed the same pattern as plasma TG with PSY consumption and decreased by an average of 12% in men (P <.05), but increased by 10% in PMW (P <.05). These reductions in apoproteins suggest an increased peripheral removal of TG in men, perhaps due to decreased insulin resistance, while in PMW, the increases in apoproteins may be related to an enhanced VLDL production. The lack of effect of PSY on VLDL metabolism in premenopausal women could be associated with the protective effect of estrogen. No prominent changes in VLDL and LDL composition were observed with PSY intake other than an increase in LDL phospholipid (P <.05). In addition, compared with men and PMW, the amount of TG per VLDL particle was less, and VLDL diameter was smaller in premenopausal women (P <.05). These results indicate an important role of sex and hormonal status in determining the effects of PSY on lipoprotein metabolism.     

Influence of triglyceride concentration on the relationship between lipoprotein cholesterol and apolipoprotein B and A-I levels

A sample of 2,103 men aged 47 to 76 years from the Québec Cardiovascular Study cohort was examined to quantify the influence of plasma triglyceride (TG) levels on the relationship between plasma lipoprotein cholesterol and either apolipoprotein A-I (apo A-I) or apo B concentrations. Regression analyses between high-density lipoprotein cholesterol (HDL-C) and apo A-I through TG tertiles showed highly significant correlations (.62 < or = r < or = .75, P < .0001) in all TG tertiles between these 2 variables. The associations for plasma apo B versus low-density lipoprotein cholesterol (LDL-C) and non-HDL-C levels were also studied on the basis of TG concentrations, and correlation coefficients between either LDL-C or non-HDL-C and apo B were essentially similar among TG tertiles (.78 < or = r < or = .85 and .83 < or = r < or = .86 for LDL-C and non-HDL-C, respectively, P < .0001). Regression analyses also showed that lower HDL-C levels were found for any given apo A-I concentration among men in the 2 upper TG tertiles, whereas lower LDL-C concentrations were observed at any given apo B level among subjects in the upper TG tertile. We further investigated whether there were synergistic alterations in the HDL-C/apo A-I and LDL-C/apo B ratios as a function of increasing plasma TG. A significant association was noted between these 2 ratios (r = .37; P < .0001). Mean HDL-C/apo A-I and LDL-C/apo B ratios were then calculated across quintiles of plasma TG concentrations. Increased TG concentrations were first associated with a reduced HDL-C/apo A-I ratio, followed by a decreased LDL-C/apo B ratio. These results suggest that a relatively modest increase in TG may rapidly alter the relative cholesterol content of HDL particles. Finally, the cholesterol content of the non-HDL fraction appears to be influenced less by TG levels than HDL-C and LDL-C fractions. Thus, the plasma apo B-containing lipoprotein cholesterol level may provide a better index of number of atherogenic particles than the LDL-C concentration, particularly in the presence of hypertriglyceridemia (HTG).     

Predictive value of plasma apolipoprotein B in myocardial infarction in young subjects. Correlations with coronarographic data

In recent epidemiological studies, apolipoprotein-B (apo B), the main low density lipoprotein (LDL), was found to be significantly elevated in patients with early atherosclerosis. The aim of this study was to compare plasma apo B in a population of men who had suffered myocardial infarction before 45 years of age (N = 31) with a control population (N = 22). In the coronary group, there were 27 angiographies between the end of the first and third month. The plasma lipoproteins were separated by ultracentrifugation, cholesterol and triglycerides measured by enzymatic methods and apo B by Laurell's technique of immunoelectrophoresis. Our results showed significantly higher apo B in the coronary group (p less than 0.05). Serum cholesterol, triglycerides, very low density lipoprotein (VLDL) and LDL cholesterol were also significantly higher whilst high density lipoprotein (HDL) cholesterol was significantly lower. In addition, apo B levels correlated with the severity of the coronary lesions on angiography. Therefore, the plasma apo B level is a good predictive indicator of the presence of early coronary atherosclerosis and its severity.     

Plasma lipoproteins and regulation of hepatic metabolism of fatty acids in altered thyroid states

This article reviews our understanding of effects of thyroid hormone excess and deficiency on hepatic metabolism of FFA, and consequent effects on production, secretion, and metabolism of plasma lipoproteins. In the hyperthyroid state the following alterations are observed. Fatty acid oxidation and ketogenesis are stimulated simultaneously with a paradoxical stimulation of fatty acid synthesis, which may be linked by virtue of a blunted response of mitochondrial carnitine palmitoyltransferase I (CPT-I) to malonyl coenzyme A (CoA). Esterification of fatty acid to triglyceride (TG) is reduced, as is the secretion of the very low density lipoprotein (VLDL) (including VLDL TG, cholesterol, and apoprotein); this may be due, in part, to decreased concentrations of glycerol-3-phosphate (G3P) in the hepatic cell. In the intact animal or patient, however, serum TG concentration is variable, which may reflect increased adipose tissue lipolysis and elevated concentrations of plasma FFA, which would tend to drive VLDL secretion by the liver. Clearance of the VLDL and its metabolic product, the low density lipoprotein (LDL), is increased, resulting in decreased plasma total and LDL cholesterol. Although high density lipoprotein (HDL) cholesterol may also be reduced, the ratio of LDL/HDL cholesterol is further decreased. The regulatory role of the lipoprotein apoproteins is less clear, but hepatic apolipoprotein (apo) B secretion (required for VLDL) is diminished, while apo-AI secretion (required for HDL) is stimulated, perhaps both reflecting rates of synthesis. Plasma concentrations of apo-AI are variable, dependent on relative rates of secretion and clearance. In the hypothyroid, many of these effects are reversed, which results in hyperlipoproteinemias and greater risk for the development of atherosclerotic cardiovascular disease.     

Effect of melatonin on cholesterol absorption in rats

This study evaluated the influence of melatonin on cholesterol absorption in rats fed on high cholesterol diet (HCD). HCD induced a remarkable increase in hepatic and plasma total cholesterol, plasma very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, a decrease in high density lipoprotein (HDL) cholesterol and an elevation in triacylglyceride (TG) levels in plasma and in the liver. Melatonin suspension (10 mg/kg), specially prepared for this purpose, cholestyramine (230 mg/kg) and ezetimibe (145 microg/kg) were administered orally to the rats fed HCD for 30 days. Melatonin significantly reduced cholesterol absorption in rats fed on HCD and caused significant decreases in total cholesterol, TG, VLDL- and LDL-cholesterol in the plasma and contents of cholesterol and TG in the liver. The level of HDL cholesterol was significantly increased after melatonin. These results suggested that inhibition of cholesterol absorption caused by melatonin could be a mechanism contributing to the positive changes in plasma cholesterol, lipoprotein profile and the lipid contents in the liver.     

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.     

Long-term exercise training with constant energy intake. 3: Effects on plasma lipoprotein levels

The composition and concentration of plasma lipoproteins were studied in five young men (mean BMI = 27.5 +/- 2.9 (s.d.] before, during (after 25 and 50 days of training), and after the completion of a 100 day exercise training program that induced daily 4.2 MJ calorie deficit. Along with reductions in body weight (from 86.7 +/- 20.0 to 78.7 +/- 17.1 kg, P less than 0.01) and in fat mass (from 17.0 +/- 9.7 to 10.4 +/- 7.4 kg, P less than 0.01), the exercise training program induced numerous changes in plasma lipoprotein levels. Plasma total cholesterol level fell significantly after 25 days of training (P less than 0.05) and remained significantly reduced at the end of the training experiment (P less than 0.05). This reduction in total plasma cholesterol was accompanied by reductions in plasma apoprotein (apo) B, LDL-cholesterol and LDL-apo B levels (P less than 0.05). There were trends for reductions in plasma triglyceride and VLDL components that were significant only for VLDL-triglycerides (P less than 0.05). Plasma HDL-cholesterol levels increased significantly only at the end of the training program (P less than 0.01). This increase in plasma HDL-cholesterol was not accompanied by an increase in plasma apo A-I levels suggesting that exercise training produced an increase in HDL cholesterol content rather than an increase in HDL particle number. Ratios of HDL-cholesterol/cholesterol (P less than 0.01) and apo A-I/apo B (P less than 0.05) were significantly increased by exercise training, suggesting a decreased risk of cardiovascular disease. These results indicate that a reduction in fat mass solely induced by aerobic exercise training has substantial beneficial effects on plasma lipoprotein levels.     

Marked decrease of apolipoprotein A-V in both diabetic and nondiabetic patients with end-stage renal disease

Apolipoprotein (apo) A-V has been the focus of significant attention as a potential modulator of plasma triglyceride (TG) in spite of its very low plasma concentration. TG levels are frequently elevated in patients with end-stage renal disease (ESRD), which is associated with a high prevalence of cardiovascular disease among them. We measured plasma apo A-V levels in 20 control subjects and 70 patients with diabetic and nondiabetic ESRD to investigate whether low apo A-V levels could be involved in the pathogenesis of the hyper-TG in ESRD. The plasma TG levels were significantly elevated in diabetic patients with ESRD, whereas those in nondiabetic ESRD patients remained similar to those in the controls. High-density lipoprotein cholesterol levels were significantly lower in the patients with ESRD than in the controls, irrespective of the presence of diabetes. Apo A-V levels measured by an enzyme-linked immunosorbent assay were markedly reduced to 40% to 44% of the control levels in both diabetic and nondiabetic patients with ESRD. The apo A-V levels were not correlated with TG in the overall study population, but they were positively correlated with high-density lipoprotein cholesterol. These results suggest that reduced apo A-V levels do not necessarily lead to hyper-TG in ESRD, but we are unable to exclude the possibility that low apo A-V plays a role in raising the TG level in diabetic ESRD.     

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.     

Pravastatin sodium, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreases serum total cholesterol in Japanese White rabbits by two different mechanisms

Pravastatin sodium (pravastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), when orally administered to male Japanese White (JW) rabbits at 1-30 mg/kg for 21 days, decreased the concentrations of total cholesterol, low density lipoprotein (LDL)-cholesterol and high density lipoprotein (HDL)-cholesterol in a dose-dependent manner. On the other hand, pravastatin did not change the concentration of serum triglycerides and very low density lipoprotein (VLDL)-cholesterol. On day 21, LDL-cholesterol was significantly decreased at doses higher than 3 mg/kg, whereas HDL-cholesterol was significantly reduced at doses higher than 10 mg/kg. The concentrations of hepatic LDL receptor proteins determined by immunoblot analysis increased at the same dose at which the concentrations of LDL-cholesterol decreased. The serum concentrations of HDL-cholesterol were decreased at the same dose at which VLDL-cholesterol secretion rates from the liver were reduced. The present study suggests that in JW rabbits, pravastatin decreases the serum concentration of LDL-cholesterol through an LDL receptor pathway, whereas the agent lowers the concentration of HDL-cholesterol by the mechanisms associated with a reduction of VLDL-cholesterol secretion from the liver.     

Lipid metabolism in nephrotic rats induced by daunomycin injection

Lipid metabolism in the blood and liver of rats was investigated to clarify the mechanism of dyslipoproteinemia in the nephrotic syndrome. The nephrotic syndrome was induced in rats by a single injection of daunomycin. The serum total cholesterol, triglyceride, and phospholipid levels in nephrotic rats 14 days after the injection were increased 3.1-fold, 2-fold, and 2.7-fold, respectively, over the control values. The cholesterol, triglyceride, and phospholipid contents of high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) were also increased, increase in VLDL lipids being the greatest. The serum HDL cholesterol level decreased gradually after day 14, returning to the normal level on day 37, whereas the LDL and VLDL cholesterol levels continued to increase until day 37. The mechanism of dyslipoproteinemia in the nephrotic syndrome was examined by comparing lipid metabolism in the liver of nephrotic rats induced by daunomycin with that of rats fed on high-cholesterol diet. The contents of to total lipids, triglyceride, and cholesterol ester in the liver were significantly less in nephrotic rats than in controls. The contents of total lipids and cholesterol ester in the liver were much higher in rats fed on high-cholesterol diet than in controls. The contents of total lipids, triglyceride, cholesterol ester, and phospholipid in the liver were significantly lower in nephrotic rats fed on high-cholesterol diet than in normal rats fed on high-cholesterol diet.(ABSTRACT TRUNCATED AT 250 WORDS)