Intermediate Density Lipoprotein Levels Research Articles

Advanced Oxidation Protein Products Are Strongly Associated with the Serum Levels and Lipid Contents of Lipoprotein Subclasses in Healthy Volunteers and Patients with Metabolic Syndrome.

The association between advanced oxidation protein products (AOPPs) and lipoprotein subclasses remains unexplored. Therefore, we performed comprehensive lipoprotein profiling of serum using NMR spectroscopy and examined the associations of lipoprotein subclasses with the serum levels of AOPPs in healthy volunteers (HVs) and patients with metabolic syndrome (MS). The serum levels of AOPPs were significantly positively correlated with the serum levels of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL); however, they were significantly negatively correlated with high-density lipoprotein (HDL). These lipoproteins (and their subclasses) differed markedly regarding the direction of correlations between their lipid contents and AOPPs. The strength of the correlations and the relative contributions of the subclasses to the correlations were different in the HVs and patients with MS. As revealed by orthogonal partial least squares discriminant analyses, the serum levels of IDL were strong determinants of AOPPs in the HVs, whereas the serum levels of VLDL and the lipid content of LDL were strong determinants in both groups. We conclude that IDL, VLDL, and LDL facilitate, whereas HDL diminishes the bioavailability of serum AOPPs. The presence of MS and the lipid contents of the subclasses affect the relationship between lipoproteins and AOPPs.

Lipoprotein subfractions in patients with sarcopenia and their relevance to skeletal muscle mass and function.

Loss of skeletal muscle mass is a characteristic of aging. Growing evidence suggests the role of fatty acids and their derived lipid intermediates in the regulation of skeletal muscle and function. However, the exact association between lipoprotein subfractions and sarcopenia in elderly individuals remains unclear. In this study, we aimed to investigate the levels of lipoprotein subfractions in sarcopenia patients and their relationship with skeletal muscle mass and function. A total of 84 elderly Chinese subjects aged ≥65years who did not have diseases that obviously affected lipid metabolism were included. Concentrations of lipoprotein subfractions, including total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), HDL2, HDL3, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), VLDL3, LDL-particle (LDL-P), lipoprotein(a) and remnant-like particle cholesterol (RLP-C), were determined by vertical auto profile. Triglyceride (TG) was measured by an enzymatic colorimetric assay. The skeletal muscle index (SMI) was assessed by bioelectrical impedance analysis. Handgrip strength was measured using a hand-held dynamometer. The levels of TC, TG, LDL-C, LDL-P, IDL, VLDL, VLDL3, RLP-C and C-reactive protein were significantly higher in sarcopenia patients than in controls (p<0.05). Pearson Product-Moment Correlation Coefficient analysis showed that the TC, TG, LDL-C, IDL, VLDL, VLDL3, and RLP-C levels were negatively associated with the SMI; The TG, IDL, VLDL, VLDL3, and RLP-C were negatively correlated with handgrip strength. In multivariate stepwise regression analysis, the VLDL and RLP-C levels were significantly correlated with the SMI. The sensitivity and specificity of the combined measurement of VLDL and RLP-C in predicting sarcopenia were 69.8% and 92.5% (AUC: 0.831; 95% CI:(0.739, 0.924); p<0.05). The occurrence of sarcopenia is associated with disorders of lipid metabolism, particularly VLDL and RLP-C.

Correlation between Ischaemia-Modified Albumin and Intermediate-Density Lipoprotein in Haemodialysis Patients with End-Stage Renal Disease

This study investigated the association between ischaemia-modified albumin (IMA), a biomarker of cardiac ischaemia, and increases in the levels of intermediate-density lipoprotein (IDL), an atherogenic particle that can cause oxidative stress, in haemodialysis patients with end-stage renal disease (ESRD). Fasting levels of serum IMA and lipids/lipoproteins were analysed in 15 patients and 15 healthy control subjects. There was a close positive correlation between IMA and IDL levels in ESRD patients but no significant correlation between IMA and lipids/lipoproteins in control subjects. This suggests a possible link between the characteristic dyslipoproteinaemia found in ESRD and levels of IMA and, if confirmed in studies with larger sample sizes, may lead to further studies on the potential of the relationship between IMA and IDL as a biomarker in haemodialysis patients with ESRD.

A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy

Lipoprotein glomerulopathy (LPG) is considered a type of renal lipidosis, characterized by the presence of lipoprotein thrombi in markedly dilated capillary lumina of the affected glomeruli [1]. LPG is a rare disease; approximately 65 cases have been reported to date [2]. Patients with LPG exhibit proteinuria and progressive renal dysfunction. In most of the LPG patients, levels of intermediate-density lipoproteins are elevated, resembling type III hyperlipoproteinaemia; moreover, apolipoprotein E (ApoE) levels are also elevated. Recent genetic studies have revealed that several ApoE gene mutations are associated with LPG [3]. In this study, we report a LPG patient with a novel ApoE mutation, without plasma lipid and lipoprotein abnormalities or elevated ApoE level.

Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib on Apolipoprotein B100 Metabolism in Humans

Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins. Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production. These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.

Altered lipoprotein subclass distribution and PAF-AH activity in subjects with generalized aggressive periodontitis

In this study, we examined whether the documented increase of plasma triglycerides in patients with generalized aggressive periodontitis (GAgP) is associated with changes in lipoprotein subclass distribution and/or LDL-associated platelet-activating factor acetylhydrolase (PAF-AH) activity. Lipoprotein subclasses were analyzed in whole plasma samples using nuclear magnetic resonance methods. Compared with subjects without periodontitis (NP subjects; n = 12), GAgP subjects (n = 12) had higher plasma levels of large, medium, and small VLDL (35.0 +/- 6.7 vs. 63.1 +/- 9.6 nmol/l; P = 0.025), higher levels of intermediate density lipoprotein (24.8 +/- 11.6 vs. 87.2 +/- 16.6 nmol/l; P = 0.006), lower levels of large LDL (448.3 +/- 48.5 vs. 315.8 +/- 59.4 nmol/l; P = 0.098), and higher levels of small LDL (488.2 +/- 104.2 vs. 946.7 +/- 151.6 nmol/l; P = 0.021). The average size of LDL from NP and GAgP subjects was 21.4 +/- 0.2 and 20.6 +/- 0.3 nm, respectively (P = 0.031). Compared with NP subjects, GAgP subjects had a greater number of circulating LDL particles (961.3 +/- 105.3 vs. 1,349.0 +/- 133.2 nmol/l; P = 0.032). Differences in the plasma levels of large, medium, and small HDL were not statistically significant. NP and GAgP subjects had similar plasma levels of total LDL-associated PAF-AH activity; however, LDL of GAgP subjects contained less PAF-AH activity per microgram of LDL protein (1,458.0 +/- 171.0 and 865.2 +/- 134 pmol/min/microg; P = 0.014). These results indicate that, in general, GAgP subjects have a more atherogenic lipoprotein profile and lower LDL-associated PAF-AH activity than NP subjects. These differences may help explain the increased risk of GAgP subjects for cardiovascular disease.

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< d<1.045 g/ml) and LDL2 (1.045< d<1.063 g/ml), and high-density lipoprotein (HDL)2 (1.063< d<1.125 g/ml) and HDL3 (1.125< d<1.210 g/ml) subfractions, and apolipoproteins, and the activities of lipoprotein-metabolizing enzyme before and after treatment. All three treatments significantly lowered the plasma levels of total cholesterol, LDL1 cholesterol, and apolipoprotein B, C-II, and E. In combination therapy, significantly reduced levels of VLDL, IDL, and LDL2 cholesterol were also obtained. Combination therapy lowered total and LDL1 cholesterol significantly more than did estrogen alone. Estrogen and combination therapy significantly increased the levels of cholesterol in the HDL2 subfraction, triglyceride in the HDL2 and HDL3 subfractions, and apolipoprotein A-I and A-II. Estrogen treatment, but not combination therapy, also significantly raised the levels of total and IDL triglyceride. Estrogen and combined therapies significantly lowered the activities of hepatic triglyceride lipase and lecithin cholesterol acyltransferase. Findings indicate that combination therapy with estrogen plus simvastatin favorably affected lipid metabolism by reducing the concentrations of VLDL and IDL particles as well as large and small LDL particles, increasing the concentration of HDL particles, and preventing estrogen-induced increases in plasma triglyceride levels.

Effects of lipid-lowering drugs on intermediate-density lipoprotein in uremic patients

Patients with chronic renal failure often have alterations in lipoprotein profile including elevated very-low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL), and reduced high density lipoprotein (HDL) levels. Among these changes, raised IDL has been shown as an independent risk factor for atherosclerosis in hemodialysis patients. There are a limited number of studies reporting pharmacological approaches to IDL reduction in a uremic population. We therefore summarize the effects of lipid-lowering drugs on IDL levels in patients with chronic renal failure treated by hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). First, a nicotinic acid analog niceritrol was given to hemodialysis patients. The drug increased HDL-cholesterol by 11%, but the reductions in VLDL-, IDL- and LDL-cholesterol were not significant. Second, CAPD patients were treated with a fibric acid derivative clinofibrate, which was excreted mainly into bile unlike other drugs in this class. The fibrate resulted in a remarkable reduction in VLDL-triglycerides, although it did not reduce IDL-cholesterol. Finally, an HMG-CoA reductase inhibitor (statin) pravastatin was used in HD and CAPD patients. Pravastatin reduced IDL- and LDL-cholesterol to the same extent (by 31%). None of these treatments caused serious adverse effects. We propose that IDL is an important target in the management of uremic dyslipidemia. To date, statins have been shown to be suitable for this purpose, although it remains to be clarified whether such an intervention reduces the risk for atherosclerotic vascular events in the uremic population.

Lipoprotein abnormalities in diabetic nephropathy

The risk of death from coronary heart disease (CHD) is substantially increased in diabetic nephropathy compared with normal subjects or diabetes without nephropathy. I tried to define abnormal plasma lipoproteins profiles contributing to the increased CHD risk in diabetic nephropathy. This study included: middle-aged to older type 2 diabetic patients with normoalbuminuria, microalbuminuria, and overt albuminuria; nondiabetic patients with primary renal disease; and normal control subjects. Triglyceride (TG) levels were significantly increased in type 2 diabetic patients with microalbuminuria and overt proteinuria. Glycemic control or insulin resistance were not associated with TG levels. Intermediate-density lipoprotein (IDL) and remnant-like particle (RLP) cholesterol in type 2 diabetics were significantly elevated in patients with overt nephropathy. Hepatic TG lipase (HTGL) was significantly decreased in diabetic nephropathy, and their higher IDL levels were inversely related to decreased HTGL. Low-density lipoprotein (LDL) size was significantly smaller in diabetic nephropathy compared with nondiabetics with kidney disease. The TG response after the oral fat load was significantly greater in diabetic nephropathy, and the LDL size was inversely associated with the magnitude of postprandial lipemia. Microalbuminuric diabetic patients had a lower lipoprotein lipase (LPL) mass and a higher von Willebrand factor (vWF), an indicator of endothelial cell damage, than normoalbuminuric patients. The LPL mass was inversely associated with vWF, suggesting that widespread endothelial cell damage results in a reduction in LPL bound to endothelium in diabetic subjects with microalbuminuria. Plasma lipoprotein profiles become more atherogenic in patients with diabetic nephropathy, including the subclinical stage, compared with diabetics without nephropathy or those with nondiabetic kidney disease.

Atherogenicity of Triglyceride-Rich Lipoproteins

There is increasing evidence that alterations in metabolism of triglyceride-rich lipoproteins are of importance in the pathogenesis of atherosclerosis and its clinical consequences. Particles with the characteristics of triglyceride-rich lipoprotein remnants have been related to the extent and severity of atherosclerosis in humans and in animal models. These particles can be identified using ultracentrifugal procedures as small, very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) with Svedberg flotation rates (S f) of 12–60. Postprandial triglyceride levels also have been related to risk of coronary artery disease, consistent with a pathologic role for remnant lipoproteins. In studies in which measurements of lipoprotein subfractions have been carried out, levels of IDL have been more predictive than low-density lipoprotein (LDL) of atherosclerosis progression as assessed by coronary artery angiography or carotid artery ultrasonography. These findings suggest that a considerable portion of the coronary disease risk attributed to LDL may be accounted for by the IDL particles included in standard LDL measurements. Other metabolic changes associated with increased levels of plasma triglyceride may also adversely affect cardiovascular disease risk. These include reductions in HDL-cholesterol and apoprotein A1, increased levels of small dense LDL particles, redistribution of apoC-III from HDL to apoB-containing lipoproteins, diminished insulin sensitivity, and procoagulant changes, including increased levels of the fibrinolysis inhibitor, plasminogen-activator inhibitor-1 (PAI-1). A predominance of small dense LDL (subclass pattern B) is a discrete marker for this cluster of interrelated abnormalities and is found in 40–50% of patients with coronary artery disease. Therapeutic interventions with favorable effects on components of this dysmetabolic profile appear to be of value in decreasing atherosclerosis risk in a substantial proportion of the population.

Specific reduction of plasma large, light low-density lipoprotein by a bile acid sequestering resin, cholebine (MCI-196) in type II hyperlipoproteinemia

The effect of a bile acid sequestrant, cholebine (3 g/day), on plasma lipoprotein subfractions was investigated in 16 patients with type II hyperlipoproteinemia. Activities of low density lipoprotein (LDL)-receptor and activities of lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) were assayed to address the mechanism of cholebine-induced changes in plasma lipoprotein subfractions. Twelve weeks of treatment with cholebine reduced plasma levels of total cholesterol (TC) and LDL-cholesterol (C) by 8.3±8.1% (mean±S.D.) and 14.4±11.9%, respectively ( P<0.001), but did not affect plasma levels of high density lipoprotein (HDL)-C. Cholebine significantly reduced plasma levels of LDL 1-C (1.019< d<1.045) by 22.9±18.9% ( P<0.001) but did not affect plasma levels of very low density lipoprotein (VLDL)-C, intermediate density lipoprotein (IDL)-C, LDL 2-C (1.045< d<1.063), HDL 2-C, and HDL 3-C ( d>1.125). Gradient polyacrylamide gel electrophoresis (PAGE) revealed that cholebine reduced large LDL in plasma but had almost no effects on small LDL and HDL subfractions. Cholebine did not alter the activities of LCAT and CETP. LDL-receptor activities of cultured lymphocytes negatively correlated with the reduction in plasma levels of LDL-C ( r=−0.500, P<0.05), IDL-C ( r=−0.581, P<0.02), and LDL 1-C ( r=−0.610, P<0.01), respectively. Thus, cholebine seems to reduce further the plasma levels of IDL and large, light LDL in patients with lower LDL-receptor activities. We conclude that cholebine only reduces plasma levels of large, light LDL. This may be due to the stimulation of hepatic LDL-receptor activity.

Remnant-like particle cholesterol may indicate atherogenic risk in patients on chronic hemodialysis.

Recently, involvement of remnant-like particle cholesterol (RLP-C) in atherosclerosis was reported, but this parameter has not been adequately investigated in hemodialysis (HD) patients. The present study investigated the relationship between the RLP-C level and total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), lipid peroxides (malone dialdehyde, MDA), apolipoprotein (Apo) A-I, and ApoB. In addition, the fractions of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), LDL, and HDL in serum lipoproteins were determined by disk polyacrylamide gel electrophoresis. The relationship between the RLP-C level and three atherogenic indices was also studied. The RLP-C level in HD patients (8.2 +/- 6.7 mg/dl) was significantly higher than that in normal controls (2.7 +/- 1.3 mg/dl). The RLP-C level showed a significant positive correlation with the levels of TC, TG, LDL-C, MDA, ApoB, VLDL(%), and IDL(%), as well as a negative correlation with HDL(%). However, there was no correlation with age or the duration of HD. RLP-C also showed significant positive correlations with the (TC -HDL-C)/HDL-C ratio and the (VLDL + LDL)/HDL ratio, as well as a negative correlation with the ApoA-I/ApoB ratio. These results suggest that RLP-C may be a potential indicator of atherogenic risk in HD patients.

Modification of VLDL apoprotein B by acetaldehyde alters apoprotein B metabolism

Acetaldehyde (AcA), the first metabolite in ethanol oxidation, is chemically highly reactive and forms adducts with proteins in alcoholics. We examined the effect of very low density lipoprotein (VLDL) apoprotein B (apoB) modification by AcA on the metabolism of apoB-containing lipoproteins [VLDL, intermediate density lipoprotein (IDL) and low density lipoprotein (LDL)]. VLDL-B was selectively radiolabelled with either 125I or 131I and modified with various AcA concentrations, and the preparation was injected into rabbits simultaneously with control-treated VLDL. AcA modification of VLDL-B reduced the fractional catabolic rates for VLDL-B, IDL-B, and LDL-B. The direct removal of VLDL-B from plasma was decreased, whereas the fraction of VLDL-B converted to IDL-B was increased. The effect of AcA modification on the overall fraction of VLDL converted to LDL was qualitatively heterogeneous: VLDL-B modification with 2.0 mM AcA reduced the fraction converted, whereas modification with 4.0 and 8.0 mM AcA increased it. The concentrations of AcA used were higher than those reported in blood after ethanol ingestion, but the experiments serve to test in qualitative terms the model of VLDL-B modification by AcA. The observed VLDL-B alteration by AcA in vivo in alcoholics is most likely to be close to the minor modification used here, thereby theoretically contributing to the low IDL and LDL levels observed in alcoholics.

Plasma lipoproteins in familial dysbetalipoproteinemia associated with apolipoproteins E2(Arg158--&gt;Cys), E3-Leiden, and E2(Lys146--&gt;Gln), and effects of treatment with simvastatin.

Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with familial dysbetalipoproteinemia (FD) who had apolipoprotein (apo) E2(Arg158-->Cys) homozygosity (the E2-158 variant, n = 6), apoE3-Leiden heterozygosity (the E3-Leiden variant, n = 6), or apoE2(Lys146-->Gln) heterozygosity (the E2-146 variant, n = 6), with average plasma cholesterol concentrations of 8.99 +/- 1.34 mmol/L, 9.29 +/- 1.55 mmol/L, and 8.46 +/- 1.10 mmol/L, respectively. No significant differences in sex, age, body mass index, dietary habits, and standard laboratory tests between the three groups were observed. The lipoprotein profiles of all FD patients were characterized by higher concentrations of very-low-density lipoprotein (VLDL) 1, VLDL2, and intermediate-density lipoprotein (IDL) and a higher cholesteryl ester content of VLDL1 and VLDL2 than in 6 normolipidemic control subjects with an average plasma cholesterol concentration of 5.90 +/- 0.53 mmol/L. Major differences between the plasma lipoprotein profiles of patients with the E2-158 variant, the E3-Leiden variant, and the E2-146 variant and the normolipidemic control subjects were in IDL cholesterol concentration (1.70 +/- 0.26, 1.50 +/- 0.26, 1.05 +/- 0.36, and 0.47 +/- 0.14 mmol/L, respectively), LDL cholesterol concentration (1.83 +/- 0.50, 3.09 +/- 0.32, 3.79 +/- 0.76, and 3.77 +/- 0.56 mmol/L, respectively), and the molar ratio of IDL cholesterol to LDL cholesterol (0.98 +/- 0.28, 0.48 +/- 0.04, 0.28 +/- 0.09, and 0.12 +/- 0.03, respectively). After 10 weeks of simvastatin treatment the concentrations of plasma cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in 3 patients with the E2-158 variant fell significantly, by 46%, 56%, 53%, and 48%, respectively; they also fell in 3 patients with the E3-Leiden variant, by 48%, 54%, 57%, and 52%, respectively, and in 3 patients with the E2-146 variant, by 38%, 55%, 46%, and 35%, respectively. Simvastatin therapy lowered plasma activity of cholesteryl ester transfer protein but had no significant effect on plasma activity of lecithin:cholesterol acyltransferase. It is concluded that patients with FD due to various apoE variants have different lipoprotein profiles, mainly with regard to IDL and LDL levels, although they have a number of similar features of dysbetalipoproteinemia. Simvastatin therapy effectively reduced the plasma concentrations of total cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in the three groups of patients studied. It is proposed that apoE-dependent defects of the conversion of IDL to LDL may be an important mechanism in the pathophysiology of FD.

Of mice, men and cholesterol

We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR−/− mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type littermates, owing to a seven- to ninefold increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for intravenously administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of 125I-HDL was normal in the LDLR−/− mice. Unlike wild-type mice, LDLR−/− mice responded to moderate amounts of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR−/− mice was reduced to normal 4 d after the intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. We conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.

Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.

We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-/- mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type litter-mates, owing to a seven- to ninefold increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for intravenously administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of 125I-HDL was normal in the LDLR-/- mice. Unlike wild-type mice, LDLR-/- mice responded to moderate amounts of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR-/- mice was reduced to normal 4 d after the intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. We conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.

Lipoproteins in familial dysbetalipoproteinemia. Variation of serum cholesterol level associated with VLDL concentration.

Patients with familial dysbetalipoproteinemia (FD) associated with the apo E2/2 phenotype exhibit a marked interindividual variability in serum cholesterol and triglyceride concentrations. It has been proposed that this variability is due to a combination of the apo E2/2 phenotype and additional genetic factors implicated in diseases like familial hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypertriglyceridemia. To further explore the nature of this variability, the lipoprotein profiles of 17 patients with FD associated with the apo E2/2 phenotype were analyzed by a density-gradient ultracentrifugation technique and by 2-16% polyacrylamide gel electrophoresis. It was found that all patients with FD were characterized by 1) markedly increased cholesterol concentrations of large very low density lipoprotein (VLDL) (VLDL1) (2.98 +/- 3.08 versus 0.08 +/- 0.03 mmol/L), small VLDL (VLDL2) (4.68 +/- 1.93 versus 0.27 +/- 0.13 mmol/L), and intermediate density lipoprotein (IDL) (2.25 +/- 0.72 versus 0.39 +/- 0.16 mmol/L); 2) decreased low density lipoprotein (LDL) cholesterol level (1.84 +/- 0.54 versus 3.36 +/- 0.53 mmol/L); and 3) altered composition (enrichment by cholesteryl ester) of VLDL1 and VLDL2 compared with normolipidemic control subjects. The cholesterol levels of IDL and LDL showed minor interindividual variabilities and were not correlated with serum cholesterol and triglyceride levels. The compositions of VLDL1 and VLDL2 were independent of the concentrations of lipids in serum. However, the cholesterol concentrations of VLDL1 and VLDL2 showed considerable interindividual variabilities and were positively correlated with the serum cholesterol concentration (r = 0.84 and r = 0.95, respectively, both p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Heterozygous lipoprotein lipase deficiency due to a missense mutation as the cause of impaired triglyceride tolerance with multiple lipoprotein abnormalities.

In 16 members of two Austrian families affected by a missense mutation at codon 188 of the lipoprotein lipase (LPL) gene (8 heterozygous and 8 normal subjects), carrier status for the mutation as determined by DNA analysis was related to LPL activity in postheparin plasma, to the magnitude of postprandial lipemia, and to concentration, composition, and size of the major lipoprotein classes of postabsorptive plasma. Carriers exhibited clearly reduced LPL activity, normal fasting triglycerides, but pronounced postprandial lipemia. The carriers' impaired triglyceride tolerance, as evident in the postprandial state of challenge only, was associated with a fasting lipoprotein constellation characterized by (a) enrichment of HDL2 with triglycerides, (b) reduced HDL2-cholesterol, (c) enrichment of VLDL and intermediate density lipoprotein (IDL) with cholesteryl esters, (d) elevated IDL levels, and (e) small-sized LDL. Within any given individual, the degrees of expression of these characteristics were quantitatively and continuously related with each other as well as with the magnitude of lipemia and with LPL activity.

Model development to describe the heterogeneous kinetics of apolipoprotein B and triglyceride in hypertriglyceridemic subjects

The heterogeneous nature of very low density lipoprotein (VLDL) metabolism in hypertriglyceridemia gives rise to complex kinetics when labeled VLDL are traced. Analysis of such systems benefits from the simultaneous study of several metabolically discrete subfractions which are then integrated. We have studied the kinetics of VLDL and intermediate density lipoprotein (IDL) apoprotein B and triglyceride simultaneously by injecting homologous 125I-labeled VLDL1 and 131I-labeled VLDL2 and [2-3H]glycerol intravenously in three diverse type IV hyperlipoproteinemic subjects. An additional type IV subject received only [2-3H]glycerol. Specific radioactivities were measured in: VLDL1-triglyceride and -apoB, VLDL2-triglyceride and -apoB, and in each corresponding subfraction after further separation into heparin-Sepharose-bound and -unbound fractions. ApoB and triglyceride specific radioactivities were also measured in IDL. Analysis of the kinetics of apoB in the unbound fractions in VLDL1 and VLDL2 showed the presence of two pools of particles, one of which turned over rapidly. The kinetics of apoB in the bound fractions in VLDL1 and VLDL2 were, in contrast, dominated by a large slowly turning over pool of particles that resembled the kinetics of whole VLDL. Evidence of a partial precursor-product relationship between the unbound and bound fractions suggested that the former was richer in nascent-like particles, while the latter contained more remnant particles. However, triglyceride specific radioactivity curves for both unbound and bound fractions showed initial rapid rises and broad peaks, indicating that the bound fraction also contained a substantial proportion of nascent-like particles. Using multicompartmental analysis, a model was constructed to account for the kinetics of both apoB and triglyceride in all fractions of VLDL and in IDL. The model comprises two parallel delipidation pathways that supply a common remnant pool with these features: 1) multiple direct inputs of particles into plasma at VLDL2 and IDL levels; 2) heterogeneous triglyceride precursor pools leading to different rates of labeling of VLDL1 and VLDL2; 3) very substantial delipidation of VLDL2 particles prior to conversion to IDL and; 5) triglyceride production rates somewhat higher than previously reported. The inclusion in the model of the rapidly turning over pool of triglyceride-rich particles, identified in the heparin-unbound fraction, suggests that values for triglyceride production in man have been underestimated.

Intermediate density lipoprotein levels are strong predictors of the extent of aortic atherosclerosis in the St. Thomas's Hospital rabbit strain

This study assessed nonfasting cholesterol and triglyceride in plasma and in lipoproteins as predictors of the extent of aortic atherosclerosis in 2 similar groups of rabbits from the St. Thomas's Hospital strain; the lipoprotein classes studied in the 2 groups were very low (VLDL), intermediate (IDL), low (LDL), and high density lipoprotein (HDL), and Sf > 60 lipoprotein, Sf 12–60 lipoprotein, LDL and HDL, respectively. These rabbits exhibit elevated plasma levels of VLDL, IDL, and LDL, with plasma cholesterol and triglyceride of up to 23 mmol/1 and 7 mmol/l, respectively, and with up to 100% of the aortic intima bearing atherosclerosis-like lesions. In group 1 rabbits ( n = 25), univariate linear regression showed that cholesterol in plasma, LDL, IDL and in VLDL each were positively associated with the extent of aortic atherosclerosis. In group 2 rabbits ( n = 20), cholesterol in plasma, LDL and Sf 12–60, but not in Sf > 60 lipoprotein, was consistently positively associated with the extent of aortic atherosclerosis. Neither plasma triglyceride, triglyceride in lipoprotein fractions nor HDL cholesterol was associated consistently with the extent of atherosclerosis. Using step-up multiple linear regression among lipoprotein lipids, IDL and Sf 12–60 lipoprotein cholesterol were the most powerful independent predictors of the extent of aortic atherosclerosis in the 2 groups of rabbits. LDL cholesterol was the only other independent predictor. The results suggest that remnant lipoproteins, whether defined as IDL or Sf 12–60 lipoprotein, play an important causal role in atherosclerosis under conditions where plasma levels of these lipoproteins are elevated.