Hyperglycemia in normotriglyceridemic, hypercholesterolemic insulin-treated diabetic rabbits does not accelerate atherogenesis

Severely hyperlipidemic alloxan-diabetic cholesterol-fed rabbits were treated with different daily doses of insulin in order to study the effect of insulin on plasma lipids, lipoproteins and postheparin lipoprotein lipase activity. At plasma triglyceride levels of 15,000 mg/dl, untreated diabetic rabbits carried 73% (1950 mg/dl) of plasma total cholesterol in lipoproteins with a diameter larger than 75 nm (Sf greater than 400), 25% in smaller very low density lipoproteins (VLDL) and 1% in both low and high density lipoproteins (LDL, HDL). Insulin treatment greatly reduced plasma total cholesterol and triglyceride concentrations. The decrease of plasma total cholesterol concentration was paralleled by a decrease in the cholesterol of the largest lipoproteins (Sf greater than 400) and an increase in cholesterol of both smaller very low density lipoproteins and low density lipoproteins. At the same time, postheparin plasma lipoprotein lipase activity increased 2-8-fold. When plasma triglyceride levels were normalized by insulin treatment, the lipoprotein cholesterol distribution in diabetic cholesterol-fed rabbits was similar to that of normal cholesterol-fed rabbits. To study development of atherosclerosis, diabetic rabbits were cholesterol-fed and treated with insulin for eight weeks such that the triglyceride levels were normalized, but plasma glucose levels were still greatly elevated. Nondiabetic rabbits were cholesterol-fed simultaneously. Plasma cholesterol and triglyceride levels were similar in the two groups of rabbits, as well as cholesterol in Sf greater than 400 or smaller VLDL and cholesterol in HDL. However, LDL-cholesterol concentration in the insulin-treated diabetic rabbits was 1.5-2 times that in the nondiabetic rabbits. The two groups of rabbits developed similar degrees of atherosclerosis, as judged by aortic cholesterol content. Apparently, partially controlled diabetes in cholesterol-fed rabbits does not accelerate atherogenesis beyond that observed in nondiabetic cholesterol-fed rabbits.     

Increased cholesterol concentration in intermediate density lipoprotein fraction of normolipidemic non-insulin-dependent diabetics

There is increasing agreement about the atherogenicity of intermediate density lipoprotein (IDL). In order to determine whether normocholesterolemic diabetics are at a higher risk of atherosclerosis, cholesterol concentrations in three subclasses of triglyceride-rich lipoprotein fraction (Sf 12-400) were examined. Their plasma triglyceride and cholesterol levels were limited to below 150 and 250 mg/dl, respectively. They were divided into 3 groups according to their treatment: insulin injection (group I), sulphonylurea (group S) and diet alone (group D). Age-matched healthy normolipidemic non-obese subjects served as controls (group C). Triglyceride-rich lipoproteins were separated by ultracentrifugation: very low density lipoprotein (VLDL), Sf 60-400; intermediate density lipoprotein (IDL1), Sf 20-60; IDL2; Sf 12-20. Cholesterol concentrations in total plasma, VLDL, IDL2 and high density lipoprotein (HDL) were all identical in every group. A significant increase in cholesterol concentration was found in IDL1 of groups S and D. Low density lipoprotein-cholesterol of group I was also increased. These findings indicate an increased risk factor in normolipidemic diabetics.     

The association of increased levels of intermediate-density lipoproteins with smoking and with coronary artery disease

Studies were undertaken to determine whether there is an association between elevated levels of intermediate-density lipoproteins (IDL) (Sf 12-60 lipoproteins) and coronary artery disease. Forty-five to sixty-five-year-old men with objectively documented coronary artery disease (n = 58) who were free of known risk factors (diabetes, hypertension, obesity, hyperuricemia, and hypercholesterolemia) were compared with similar men who were free of coronary artery disease (n = 52). Smokers could not be excluded. The coronary artery disease group had a higher rate of cigarette smoking (NS, due to large variations); higher concentrations of triglycerides in their plasma (p = .003) and higher levels of very low-density lipoproteins (VLDL) (p = .007), IDL (p = .016), and low-density lipoproteins (LDL) (p = .04); as well as somewhat lower levels of high-density lipoprotein (HDL) cholesterol (p = .04). Chi-squared analysis demonstrated a strong association between coronary artery disease and IDL apolipoprotein (apo) B (p = .006), coronary artery disease and IDL triglyceride (p = .032), and coronary artery disease and IDL apo B times IDL triglyceride (p = .006) when the top quintile of the population was compared with the bottom quintile for each of these variables. Stepwise logistic regression analysis resulted in rejection of an association between coronary artery disease and HDL cholesterol, plasma triglyceride, VLDL triglyceride, or LDL triglyceride. However, it did show that coronary artery disease was most strongly associated with smoking and that the second strongest association was with IDL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of plasma triglycerides on lipoprotein patterns in normal subjects and in patients with coronary artery disease

This study examined the correlation of plasma triglyceride levels with concentrations of intermediate, low and high density lipoproteins (IDL, LDL, and HDL, respectively) and to particle sizes of LDL in 93 normal men and 106 men with coronary artery disease. Plasma triglyceride concentrations were in the normal range for all persons in both groups. Analysis of lipoproteins of density less than 1.063 g/ml was carried out by analytical ultracentrifugation. The analytical pattern gave the peak Sf for LDL as well as an indication of heterogeneity of particle sizes in the density range of LDL. In both normal subjects and patients with coronary artery disease, a positive correlation was found between peak Sf for LDL and concentrations of plasma triglycerides. Plasma triglyceride levels also were correlated positively with concentrations of Sf 20 to 60 lipoproteins and total IDL mass, and inversely with HDL cholesterol levels. Furthermore, the value for peak Sf for LDL correlated inversely with the IDL mass concentration and IDL/LDL mass ratio, and positively with the HDL cholesterol levels. The results indicate that the lipoprotein pattern, including lipoprotein concentrations and particle sizes, is sensitive to concentrations of plasma triglycerides even when the latter are within the normal range.     

Exogenous estrogens attenuate dietary hypercholesterolemia and atherosclerosis in the rabbit

The effect of exogenous estrogens upon the response to dietary cholesterol was tested in New Zealand White rabbits. Cholesterol-fed, untreated rabbits had a 10-fold increase in plasma cholesterol in 12 wk. The major increase of cholesterol occurred in very low density lipoproteins (VLDL, 43.5-fold) followed by intermediate density lipoproteins (IDL, 26-fold) and low density lipoproteins (LDL, 6-fold) with no change in high density lipoproteins (HDL). These diet induced changes were markedly attenuated in the estrogen treated animals, in whom plasma cholesterol increased only 5-fold. This increase was distributed among LDL (6-fold), IDL (7.5-fold), and VLDL (9-fold), similarly with no change in HDL. All the lipoproteins in both groups of animals were considerably enriched in cholesterol during cholesterol feeding as indicated by a high cholesterol/protein and cholesterol/triglyceride ratio. However, these ratios were lower in estrogen treated animals. There were no differences in the feed consumption, body weight or cholesterol absorption between the two groups of animals. Rabbits fed a cholesterol-rich diet but not treated with estrogen had well developed lesions in all parts of the aorta with higher content of cholesterol and phospholipids as compared to those injected with estrogen, whose aortas were completely clear of visible atherosclerosis. Equivalent total hypercholesterolemia was induced in other estrogen-treated rabbits by feeding twice the cholesterol dietary content (0.2%) as in nonestrogen-treated animals. Aortic atherosclerosis was far more evident in the latter, which had higher proportions of cholesterol-rich lipoproteins of d < 1.006 g/ml.     

Influence of early diabetic nephropathy on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition.

The procedure of discontinuous gradient ultracentrifugation (DGU) was used to characterize the influence of early diabetic nephropathy on the composition of very low density lipoprotein (VLDL, flotation density 60-400 Svedberg (Sf) units), low density lipoprotein (LDL, flotation density 0-12 Sf) and subfractions of intermediate density lipoprotein (IDL1 and IDL2, 20-60 and 12-20 Sf, respectively). Forty-six subjects with type 1 (insulin-dependent) diabetes and serum creatinine, less than 140 mumol/l were studied, of whom 23 consistently had normal rates of albumin excretion (AER less than 15 micrograms/min), and 23 had persistent albuminuria (AER 20.0-960.6 micrograms/min). The two groups were similar with respect to total serum lipids, glycaemic control, age and body mass. The composition (lipid, protein and phospholipid) and mass of VLDL, LDL and IDL2 was not appreciably altered by early nephropathy, but free and total cholesterol concentration in IDL1 (Sf 20-60) was increased (total cholesterol 0.68 (0.09) (mean (SE)) vs. 0.47 (0.07) mmol/l, and free cholesterol 0.27 (0.04) vs. 0.17 (0.03) mmol/l, both P less than 0.05). The explanation of these findings was probably an accumulation in the circulation of the remnants of chylomicron metabolism and/or intermediates in the conversion from VLDL to IDL1. In addition, there was a decrease in serum high density lipoprotein (HDL) cholesterol in early nephropathy (1.27 (0.06) vs. 1.38 (0.10) mmol/l, P less than 0.05), due to a decrease in the HDL2 cholesterol subfraction (P less than 0.05). These findings may in part explain the increased risk of premature atherosclerosis associated with the development of albuminuria.     

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.     

Overexpression of human hepatic lipase and ApoE in transgenic rabbits attenuates response to dietary cholesterol and alters lipoprotein subclass distributions

The effect of the expression of human hepatic lipase (HL) or human apoE on plasma lipoproteins in transgenic rabbits in response to dietary cholesterol was compared with the response of nontransgenic control rabbits. Supplementation of a chow diet with 0.3% cholesterol and 3.0% soybean oil for 10 weeks resulted in markedly increased levels of plasma cholesterol and VLDL and IDL in control rabbits as expected. Expression of either HL or apoE reduced plasma cholesterol response by 75% and 60%, respectively. The HL transgenic rabbits had substantial reductions in medium and small VLDL and IDL fractions but not in larger VLDL. LDL levels were also reduced, with a shift from larger, more buoyant to smaller, denser particles. In contrast, apoE transgenic rabbits had a marked reduction in the levels of large VLDLs, with a selective accumulation of IDLs and large buoyant LDLs. Combined expression of apoE and HL led to dramatic reductions of total cholesterol (85% versus controls) and of total VLDL+IDL+LDL (87% versus controls). HDL subclasses were remodeled by the expression of either transgene and accompanied by a decrease in HDL cholesterol compared with controls. HL expression reduced all subclasses except for HDL2b and HDL2a, and expression of apoE reduced large HDL1 and HDL2b. Extreme HDL reductions (92% versus controls) were observed in the combined HL+apoE transgenic rabbits. These results demonstrate that human HL and apoE have complementary and synergistic functions in plasma cholesterol and lipoprotein metabolism.     

The effect of bezafibrate on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition in type 1 diabetes associated with hypercholesterolaemia or combined hyperlipidaemia.

Lipoprotein composition was examined in type 1 diabetic subjects with hypercholesterolaemia +/- hypertriglyceridaemia during a 3-month double-blind placebo controlled assessment of bezafibrate therapy. The predominant effect was on lipoprotein lipid content. In those with hypercholesterolaemia alone, bezafibrate significantly reduced the cholesterol (particularly esterified cholesterol) and triglyceride content of large very low density lipoprotein (VLDL) (Svedberg flotation units (Sf) 60-400) in comparison to the placebo group (P less than 0.05), and a trend towards a reduction in free and esterified cholesterol within the intermediate density lipoprotein fraction (IDL) (Sf 12-20) was noted. Low density lipoprotein (LDL) composition was unaltered and in general phospholipid and protein concentrations and cholesteryl ester/protein ratios within the lipoprotein fractions were unaffected. Large VLDL cholesterol and triglyceride concentrations in those with combined hyperlipidaemia were significantly decreased following bezafibrate therapy, both in comparison to placebo-treated subjects and to baseline concentrations (P less than 0.05). An additional significant reduction in small VLDL (Sf 20-60) free cholesterol was recorded (P less than 0.05). Average reductions of large and small VLDL protein of 50-56% were not significant because of wide variation in responses. Bezafibrate had no effect on the abnormal composition of IDL and LDL, characteristic of Type 1 diabetes, regardless of whether or not hypertriglyceridaemia was associated with hypercholesterolaemia. Its major action was to lower VLDL lipid concentrations, but it may also reduce the lipid content of intermediate density lipoprotein in Type 1 diabetes.     

Metabolism of esterified cholesterol in the plasma very low density lipoproteins of the rabbit.

The in vivo metabolism of esterified cholesterol and triglyceride in plasma very low density lipoproteins (VLDL) has been studied in postabsorptive rabbits injected with endogenously 3H-labelled preparations of VLDL. The rates at which the injected esterified [3H]cholesterol and [3H]triglyceride were removed from the recipient VLDL fraction were remarkably similar. But, whereas most of the [3H]triglyceride was rapidly lost from the plasma compartment, more than 60% of the esterified [3H]cholesterol removed from VLDL was recovered in the plasma low density lipoprotein (LDL) and high density lipoprotein (HDL) fractions, an observation in direct contrast to previous findings in rats and guinea pigs in which hepatic uptake accounted for the major proportion of esterified cholesterol removed from VLDL. The appearance of VLDL-esterified [3H]cholesterol in rabbit LDL was quite compatible with the well-documented catabolic conversion of VLDL to LDL. The appearance in HDL, on the other hand, could not be so explained and was further investigated in studies performed in vitro. It was found that, concurrent with a net mass transfer of esterified cholesterol from HDL to VLDL, there was a much more rapid transfer of esterified [3H]cholesterol in the reverse direction, implying the existence of a process of molecular exchange of esterified cholesterol between the two fractions, analogous to that recently described between VLDL and LDL.     

Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase

OBJECTIVE: This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency. METHODS: We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits. RESULTS: Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006-1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04-1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits. CONCLUSIONS: We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.     

Primary prevention of atherosclerosis by lovastatin in a genetically hyperlipidaemic rabbit strain

Lovastatin, a lipid-lowering drug which inhibits cholesterol synthesis, was administered to genetically hyperlipidaemic rabbits from the age of 2 months. Twenty rabbits were selected with similar plasma cholesterol levels and divided into matched treatment and control groups. The treated animals showed a 60% decrease in plasma cholesterol due to reduced levels of low density lipoprotein (LDL) and intermediate density lipoprotein (IDL). Levels of other lipoproteins remained unchanged. In untreated animals cholesterol levels in plasma, LDL and IDL increased with age. The area of aortic atherosclerosis-like lesions was quantified after 2-10.5 months of treatment. At each time point the extent of arterial disease was profoundly less in treated than in untreated animals. The findings demonstrate that primary prevention of arterial lesions resembling human atherosclerosis (increased amounts of fibrous tissue, smooth muscle cell proliferation, foam cell formation and necrosis at the base of the plaques) results from early effective reduction of elevated plasma lipids by lovastatin in this rabbit strain.     

Effects of combination therapy with estrogen plus simvastatin on lipoprotein metabolism in postmenopausal women with type IIa hypercholesterolemia

We investigated the effects of estrogen and simvastatin, administered both alone and in combination, on the plasma lipid levels and lipoprotein-related enzymes in 45 postmenopausal women with type IIa hypercholesterolemia. They received 0.625 mg conjugated equine estrogen (n=15), 5 mg simvastatin (n=15), or the combination (n=15) daily for 3 months. We measured the concentrations of cholesterol and triglyceride in the plasma, and in the very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL)1 (1.019相似文献   

中国人血中脂类指标的随龄变化

选择513例健康人作为研究对象，根据年龄分为9组，测定其血中脂类指标．结果发现血中胆固醇（CH）、甘油三酯（TG）、低密度脂蛋白（LDL）和极低密度脂蛋白（VLDL）在出生时含量较低，以后随增龄而升高；高密度脂蛋白（HDL）在出生时较低，以后逐渐升高．到20岁之前达高峰，以后又逐渐下降，脂蛋白（a）[Lp（a）]自出生后在一生中变化不大，无明显波动；氧化型低密度脂蛋白（ox－LDL）在出生时极低，以后随增龄而升高，到70岁之前达高峰，70岁之后又有下降的趋势．相关分析也发现血CH、TG、LDL、和xo－LDL与年龄之间里明显的正相关，HDL与年纷呈负相关关系，Lp（a）与年龄之间无相关关系．以上结果提示，随着增龄，脂类代谢的变化为动脉粥样梗化的发生提供了更多的物质基础．     

Metabolism of triglyceride in rabbit plasma low and high density lipoproteins: studies in vivo and in vitro.

The metabolism of triglyceride in the plasma low density lipoproteins (LDL) and high density lipoproteins (HDL) was studied in the normal-fed rabbit. Preparations of LDL and HDL la-eled with 3H in the triglyceride moiety were obtained from donor rabbits that had previously been injected with 3H-palmitic acid. These labeled lipoproteins were subsequently either reinjected into other rabbits or incubated in vitro with unlabeled lipoprotein fractions. In vivo, there were bidirectional transfers of 3H-triglyceride between the LDL and HDL, the rate of which considerably exceeded that of any irreversible removal from the plasma compartment. To a much lesser extent, there was also a transfer of 3H-triglyceride from both LDL and HDL to very low density lipoproteins (VLDL). In vitro, so long as the dialysed 1.21 g/ml infranate of serum was present there was a significant transfer of 3H-triglyceride from both LDL and HDL into each of the other lipoprotein fractions that in no case could be accounted for by a corresponding net transfer of triglyceride mass. It was concluded that the pools of triglyceride in LDL and HDL, and to a lesser extent in VLDL, comprise parts of a larger, progressively equilibrating pool.     

Effects of atorvastatin on postprandial plasma lipoproteins in postinfarction patients with combined hyperlipidaemia

Enhanced and prolonged postprandial lipaemia is implicated in coronary and carotid artery disease. This study assessed the effects of atorvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, on postprandial plasma concentrations of triglyceride-rich lipoproteins (TRLs). Sixteen middle-aged men with combined hyperlipidaemia (baseline low density lipoprotein (LDL) cholesterol and plasma triglyceride concentrations (median (interquartile range) of 4.54 (4.17-5.26)) and 2.66 (2.04-3.20) mmol/l, respectively) and previous myocardial infarction were randomised to atorvastatin 40 mg or placebo once daily for 8 weeks in a double-blind, cross-over design. The apolipoprotein (apo) B-48 and B-100 contents were determined in subfractions of TRLs as a measure of chylomicron remnant and very low density lipoprotein (VLDL) particle concentrations (expressed as mg apo B-48 or apo B-100 per litre of plasma), in the fasting state and after intake of a mixed meal. Atorvastatin treatment reduced significantly the fasting plasma concentrations of VLDL cholesterol, LDL cholesterol and VLDL triglycerides (median% change) by 29, 44 and 27%, respectively, and increased high density lipoprotein (HDL) cholesterol by 19%, compared with baseline. The postprandial plasma concentrations of large (Svedberg flotation rate (Sf) 60-400) and small (Sf 20-60) VLDLs and chylomicron remnants were almost halved compared with baseline (mean 0-6 h plasma concentrations were reduced by 48% for Sf 60-400 apo B-100, by 46% for Sf 60-400 apo B-48, by 46% for Sf 20-60 apo B-100 and by 27% for Sf 20-60 apo B-48), and the postprandial triglyceridaemia was reduced by 23% during active treatment. In conclusion, atorvastatin 40 mg once daily causes profound reductions of postprandial plasma concentrations of all TRLs in combined hyperlipidaemic patients with premature coronary artery disease.     

Changes in plasma lipoprotein concentrations and compositions upon feeding cholesterol in high- and low-responding rhesus monkeys

When fed cholesterol, the high-responding rhesus monkeys develop severe hypercholesterolemia, whereas low-responding rhesus monkeys show only slight increases in plasma cholesterol levels. We report changes in plasma lipoprotein concentrations and compositions along with changes in plasma lipid concentrations in high- and low-responding rhesus monkeys fed a high-cholesterol diet. On low-cholesterol diet, the concentrations and compositions of plasma lipoprotein fractions were similar in the two groups. Upon feeding cholesterol, plasma very-low-density (VLDL), intermediate-density (IDL) and low-density (LDL)-lipoprotein concentrations increased in both groups, but the increases were significantly (p less than 0.01) higher in high-responders than in low-responders. Plasma HDL concentration decreased significantly (p less than 0.01) in high responders but not in low responders. In high responders, percent cholesterol increased in both VLDL and IDL fractions but in low responders, it decreased in VLDL and increased in IDL. Percent triglycerides decreased in VLDL, IDL and LDL fractions in high responders, while in low responders it tended to increase in VLDL, remained unchanged in IDL and decreased in LDL. The composition of HDL did not change in the two groups upon feeding cholesterol. Thus, when fed cholesterol, the high- and the low-responding monkeys respond distinctly differently in plasma lipoprotein concentrations and compositions. The responses occurred simultaneously, suggesting metabolic interrelationships between various lipoproteins.     

Lipoproteins in experimental nephrosis: plasma levels and composition.

Experimental nephrosis was induced in rats by administration of puromycin aminonucleoside and the levels of plasma lipoproteins were examined 7 days later and compared to controls. As determined by density ultracentrifugation, VLDL, IDL, LDL, and HDL protein levels were increased by 8, 4, 5, and 5 times, respectively. These increases were accompanied by changes in lipid and apoprotein composition. The VLDL, IDL, and LDL fractions contained less triglyceride and more phospholipid and cholesterol, while HDL lipid composition was not altered. The apoprotein composition of VLDL and IDL were not measurably altered, but LDL contained less apoE. HDL had a markedly abnormal composition characterized by an almost complete absence of apoA-IV and apoE, increased apoA-1, and decreased apoC. While increased hepatic synthesis can account for much of the observed hyperlipoproteinemia in nephrosis, the changes in lipoprotein composition suggest impaired catabolism as a contributory factor.     

Preferential reduction of very low density lipoprotein-1 particle number by fenofibrate in type IIB hyperlipidemia: consequences for lipid accumulation in human monocyte-derived macrophages

The combined (mixed) type IIB phenotype is typically associated with premature atherosclerosis and characterised by concomitant elevation of plasma levels of atherogenic triglyceride-rich lipoproteins, consisting of very low density lipoprotein (VLDL)-1 (Sf 60-400), VLDL-2 (Sf 20-60), and intermediate density lipoprotein (IDL) (Sf 12-20), as well as small dense LDL. After dietary stabilisation, type IIB patients received micronised fenofibrate (267 mg/day) for up to 12 months. At baseline (T0), patients (n=11) displayed fasting triglyceride, cholesterol and apoB levels of 308+/-13, 350+/-17 and 187+/-9 mg/dl, respectively. Micronised fenofibrate (M-fenofibrate) induced marked reductions in plasma triglyceride (TG) (-61%, P<0.0001), total cholesterol (-32%, P=0.0005) and apolipoprotein (apo) B (-33%, P<0.001) at 12 months (T12); similar effects were seen after 3 months (T3) of treatment. These changes resulted from significant reductions in VLDL-1 (-75%, P=0.00001), VLDL-2 (-46%, P=0.002) and LDL (-33%, P<0.0003); IDL concentrations were unchanged. At baseline, VLDL-1 constituted the major TG-rich lipoprotein (TRL) fraction (50% of total mass), but only 25% at T12. These drug effects were accompanied by marked increase in HDL-C (+20%, P=0.018). Quantitative changes in triglyceride-rich lipoproteins were accompanied by significant qualitative modifications in particle size and chemical composition (VLDL-1: TG, -10.7%, P<0.001; FC, +59%, P=0.0002; PL, +19%, P=0.033; VLDL-2: FC, +11%, P=0.027; IDL: FC, +14%, P=0.0004; PL, +12%, P=0.002). Reduction in the TG content of VLDL-1 was reflected in a shift of particle size distribution to smaller diameters (mean 45.4 and 42.3 nm, respectively, at T0 and T12). We evaluated the relative atherogenicity of TRL subfractions by determining their capacity, when normalised to equal particle numbers (as apoB 100 content), to induce lipid accumulation in human monocyte-derived macrophages. Among TRL subfractions, VLDL-1 (100 microg apoB/ml) possessed the highest capacity to induce macrophage lipid loading (up to sevenfold increase in TG content, P<0.001; free cholesterol, up to 1.7-fold; P<0.05). At 100 microg apoB/ml, cellular TG loading from VLDL-1 was twofold greater than that for VLDL-2 (P<0.01), and fivefold greater than for IDL (P<0.01). Despite drug-induced changes in the qualitative properties of TRL subfractions, the activity of VLDL-1, VLDL-2 and IDL as ligands which lead to induction of macrophage lipid accumulation, at equivalent particle numbers, was not detectably altered. By contrast, the fibrate-mediated reduction in the number of circulating VLDL-1 and VLDL-2 particles (four and twofold, respectively) resulted in marked decrease in cellular lipid loading. Considered together, these findings suggest that fenofibrate may act at systemic and arterial levels to reduce the cardiovascular risk associated with VLDL subfractions in patients with a combined hyperlipidemic (type IIB) phenotype. Indeed, we speculate that reductions in circulating levels of VLDL-1 and VLDL-2 may diminish intimal penetration of these particles and thus their propensity to enhance arterial macrophage lipid accumulation and foam cell formation. Finally, fenofibrate further attenuated the atherogenic lipid profile in these patients by inducing marked reduction in LDL and elevation in cardioprotective HDL.     

Plasma lipoprotein lipids in relation to the MspI polymorphism of the apolipoprotein AII gene in Caucasian men. Lack of association with plasma triglyceride concentration

Digestion of the human apolipoprotein (apo) A-II gene with the endonuclease MspI produces fragments of 3.0 or 3.7 kb, reflecting the presence or absence of a polymorphic site within an Alu sequence 3' to the gene. Patients with hypertriglyceridemia have been shown to have an increased prevalence of the 3.0 kb allele. To explore this observation further, plasma lipoprotein lipids were studied in a random sample of fasted middle-aged Caucasian men, of which 59 were 3.0 kb homozygotes, 24 were heterozygotes, and 2 were 3.7 kb homozygotes. After adjusting for the effects of age, height, weight, alcohol intake and cigarette consumption by covariance analysis, no statistically significant associations were present between genotype and the concentrations of triglyceride in whole plasma or the d less than 1.019 g/ml fraction of plasma (i.e., VLDL + IDL). Nor were the cholesterol concentrations in VLDL + IDL, low density lipoprotein (LDL, d = 1.019-1.063 g/ml), high density lipoprotein (HDL), HDL2 or HDL3 related to genotype. In an independent comparison of eight 3.0 kb homozygotes and eight 3.7 kb homozygotes (all Caucasians) drawn from a different community, genotype was unrelated to the triglyceride or cholesterol concentrations in VLDL (d less than 1.006 g/ml), IDL + LDL (d = 1.006-1.063 g/ml) or HDL, after adjustment for the effects of covariates. These results suggest that the MspI polymorphism of the apo A-II gene is not associated with genetic variation that significantly affects triglyceride transport in the majority of men.(ABSTRACT TRUNCATED AT 250 WORDS)