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PubMed1989

Effects of diets supplemented with lard fat or mackerel oil on plasma lipoprotein lipid concentrations and lipoprotein lipase activities in domestic swine.

Levels of plasma lipoproteins and lipoprotein lipase activities in post-heparin serum were measured in 24-h fasted pigs which were fed a diet containing either 21 energy % mackerel oil or 21 energy % lard fat for 8 weeks. Lipoprotein fractionation was performed separately by density gradient ultracentrifugation and agarose gel chromatography. After 8 weeks levels of plasma triacylglycerol (-62%) and cholesterol (-55%) were lower in the mackerel oil than in the lard fat-fed animals. The triacylglycerol decline was exclusively due to the VLDL fraction, while cholesterol was reduced in all lipoprotein fractions (VLDL, IDL, LDL and HDL). Lipoprotein lipase activity in post-heparin serum, taken 6 h after a meal, was 31% decreased in mackerel oil-fed animals. The results support the hypothesis that regular intake of fish oil reduces VLDL secretion.

Animals↗
PubMed1992

Associations between lipoprotein lipase gene polymorphisms and plasma correlations of lipids, lipoproteins and lipase activities in young myocardial infarction survivors and age-matched healthy individuals from Sweden.

Association studies were carried out on a sample of 87 patients from Sweden who had survived a myocardial infarction (MI) at a young age and 93 age-matched healthy individuals, to compare the impact of polymorphisms (PvuII, HindIII and Serine447-Stop) at the lipoprotein lipase (LPL) gene locus on among-individual differences in plasma lipid traits and progression of atherosclerosis. Significant linkage disequilibrium was detected between any two of these polymorphisms, with the Stop447 allele being only found on the same chromosome as the rare alleles (no cutting sites) of the PvuII and HindIII polymorphisms. In the healthy individuals, weak associations were found between genotypes of the HindIII polymorphism and triglycerides and the PvuII polymorphism and high density lipoprotein cholesterol explaining 7.4% and 5.6% of sample variance (P = 0.03 and 0.09), respectively. No associations were found between these traits and genotypes of the Serine447-Stop substitution, and thus it is unlikely to be the cause of the associations seen with the PvuII and HindIII polymorphisms even though it truncates the enzyme amino acid sequence. The presence of the rare allele, H-, of the HindIII polymorphism was associated with a smaller variance in triglycerides and both cholesterol and triglycerides in the very low density lipoprotein fraction, and with larger interdependent variation between these lipid traits, and also between LPL activity and these lipid traits. This implies that the H- allele, rather than the Stop447 allele, has the major impact on interdependence between traits which are directly or indirectly influenced by LPL activity. In the healthy individuals who were carriers of the apolipoprotein E2 allele, the inter-dependence between LPL activity and lipid traits was significantly smaller, and that between high density lipoprotein cholesterol and both cholesterol and triglycerides in the very low density lipoprotein fraction was much larger compared with non-carriers (P < 0.05). No significant associations were found between lipid traits or lipase activity and genotypes of the Serine447-Stop substitution. However, in the patients, global severity of coronary atherosclerosis at the first angiography was significantly associated with haplotype combinations of the HindIII and the Serine447-Stop polymorphisms, with the H-Stop haplotype being associated with the highest median score (P = 0.02). The data suggest that variation at the LPL gene locus is associated with a pleiotropic effect, that is not directly mediated by changes in lipids, on severity of coronary atherosclerosis.

Adult↗
PubMed1989

Appearance of multidisperse low density lipoprotein and altered lipoprotein composition in non-insulin-dependent diabetes with type IIa hyperlipoproteinemia.

The purpose of the present study is to elucidate the characteristics of lipoprotein disorders in diabetes mellitus. By analytical ultracentrifugation, non-insulin-dependent diabetic patients (NIDDM) with type IIa hyperlipoproteinemia (HLP) showed significantly higher incidence of multidisperse low density lipoprotein (LDL) than non-diabetics with type IIa HLP. Furthermore, LDL multidispersity in diabetic subjects seemed to be directly related to neither triglyceride (TG) levels in very low density lipoprotein (VLDL) nor the degree of glycemic control. Diabetics with multidisperse LDL had a lipoprotein profile that was different from the subjects with paucidisperse LDL as follows: (1) enrichment in the cholesterol content of VLDL, (2) TG-rich LDL with small flotation coefficient, (3) low cholesterol levels in high density lipoprotein2 along with enrichment in TG, and (4) high plasma concentrations of apoprotein B. Although the underlying mechanism behind the prevalence of multidisperse LDL in NIDDM with type IIa HLP remains unknown, it seems important that lipoprotein disorders in diabetics with multidisperse LDL were potentially atherogenic.

Aged↗
PubMed1992

Apolipoprotein E and lipoprotein lipase reduce macrophage degradation of oxidized very-low-density lipoprotein (VLDL), but increase cellular degradation of native VLDL.

Oxidized low-density lipoprotein (Ox-LDL) has been shown to be taken up by the macrophage-scavenger receptor at an enhanced rate in comparison to native LDL, with consequent cellular cholesterol accumulation. In the present study, we analyzed macrophage interaction with very-low-density lipoprotein (VLDL) from normolipidemic subjects (N-VLDL) that was oxidized in the presence of 10 mumol/L copper ions. Oxidized VLDL (Ox-VLDL) contained increased conjugated dienes and malondialdehyde (MDA) equivalents and showed increased electrophoretic mobility. Gradual fragmentation of VLDL apolipoproteins (apo) was noted, with apo B-100 being the first to be fragmented, followed by apo E and apo C. Degradation of Ox-VLDL by mouse peritoneal macrophages (MPM) was increased almost twofold in comparison to N-VLDL. Upon incubation of VLDL with lipoprotein lipase (LPL), the LPL-treated lipoprotein demonstrated up to 50% increased degradation by macrophages in comparison to control N-VLDL. However, the degradation of LPL-treated Ox-VLDL was decreased by up to 20% in comparison to control Ox-VLDL. Similarly, the addition of apo E to VLDL enhanced its cellular degradation by 56%, whereas a 20% reduction in the degradation of apo E-treated Ox-VLDL was demonstrated in comparison to nontreated Ox-VLDL. These results showed that LPL and apo E, two important regulatory substances in cellular metabolism of plasma lipoproteins, increased macrophage degradation of native VLDL, but reduced the degradation of Ox-VLDL. These inhibitory effects on macrophage uptake of Ox-VLDL suggest that apo E and LPL may possess antiatherogenic potential.

Animals↗
PubMed2002

Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial.

Lipoprotein subclass measurements may enhance the prediction of coronary artery disease (CAD) risk, but clinical application of such information has been hindered by the relatively laborious and time-consuming nature of laboratory measurement methods. In this study, lipoprotein subclass analyses were performed on frozen plasma samples from 241 participants in the Pravastatin Limitation of Atherosclerosis in the Coronary arteries Trial using an automated nuclear magnetic resonance technique. The objective was to determine if levels of these subclasses provided additional information on the progression of CAD, based on the change in the minimum lumen diameter, over a 3-year period. After adjustment for race, sex, age, treatment group, baseline lumen diameter, and chemically measured levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol, on-trial predictors (p <0.05) of progression included an elevated LDL particle number, and levels of small LDL and small HDL. Within treatment groups, CAD progression was most strongly related to the LDL particle number (placebo) and levels of small HDL (pravastatin). In logistic regression models that adjusted for chemically determined lipid levels and other covariates, a small LDL level > or = 30 mg/dl (median) was associated with a ninefold increased risk of CAD progression (p <0.01) in the placebo group. These results indicate that levels of various lipoprotein subclasses may provide useful information on CAD risk even if levels of traditional risk factors are known.

Anticholesteremic Agents↗
PubMed1999

A pilot study of garlic consumption shows no significant effect on markers of oxidation or sub-fraction composition of low-density lipoprotein including lipoprotein(a) after allowance for non-compliance and the placebo effect.

Our aim was to define any effects of confirmed garlic supplementation on the resistance of low density lipoprotein (LDL) to oxidation, on LDL sub-fraction composition including levels of lipoprotein(a), and on levels of circulating antibody to oxidised LDL, variables of interest in relation to cardiovascular risk. Additional tests were performed on samples collected from a double blind, randomised 6-month parallel trial in which 900 mg Kwai garlic or placebo was taken by moderately hypercholesterolaemic volunteers. Final data was analysed for 20 garlic and 11 placebo subjects with compliance of at least 75% as determined by repeat tablet counting. EDTA plasma stabilised by sucrose was stored at -70 degrees C for up to 12 months. Lipids and apolipoproteins were determined by standard methods, lipoprotein(a) by an ELISA method and LDL fraction composition by non-gradient gel electrophoresis. Oxidative resistance of LDL purified after isolation by density gradient centrifugation was assessed from oxidative resistance to copper ions determined spectrophotometrically, antibodies to oxidised LDL were determined by a microtitre plate assay and vitamin E content of plasma by HPLC. Overall lipid/lipoprotein profiles including lipoprotein(a) were unchanged as with the parent group. LDL composition showed a trend to less dense material in both placebo and garlic groups, all differences not significant. Lag time as a marker of oxidative resistance also increased in both groups, without change in vitamin E content, all differences not significant and consistent with a placebo effect. Levels of antibodies to oxidised LDL were unchanged. The results of this study do not support the hypothesis that dietary garlic supplementation decreases the susceptibility of isolated LDL to oxidation and that patterns of LDL tractions in plasma might be involved. Levels of lipoprotein(a) in plasma were also not changed. Other mechanisms of cardiovascular benefit are however not excluded.

Double-Blind Method↗
PubMed2000

The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia.

We evaluated in a double-blind randomized trial with a double-dummy design in 28 patients with primary hypertriglyceridemia, the effect of gemfibrozil (1200 mg/day) versus Omacor (4 g/day), a drug containing the n-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), on lipid and lipoprotein levels, low density lipoprotein (LDL) subfraction profile and LDL oxidizability. Both Omacor and gemfibrozil therapy resulted in a similar significant decrease in serum triglyceride (TG), very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol concentrations and an increase in high density lipoprotein (HDL) and LDL cholesterol concentrations. The increase in LDL cholesterol was due to a significant increase in cholesterol content of the relatively buoyant LDL subfractions LDL1, LDL2 and LDL3, whereas the relative contribution of the dense LDL subfractions LDL4 and LDL5 to total LDL tended to decrease. So, both therapies resulted in a more buoyant LDL subfraction profile, reflected by a significant increase of the value of parameter K (+10.3% on Omacor vs. +26.5% on gemfibrozil therapy, gemfibrozil vs Omacor P>0.05). Cu(2+)-induced oxidation of LDL was measured by continuous monitoring of conjugated dienes. After 12 weeks of Omacor treatment LDL appeared more prone to oxidative modification in vitro than LDL after gemfibrozil treatment, as measured by the significantly decreased lag time, preceding the onset of the lipid peroxidation. In both groups the rate of oxidation did not change with therapy. The amount of dienes formed during oxidation increased significantly on Omacor treatment, but not on gemfibrozil treatment. Plasma thiobarbituric acid reactive substances were higher after Omacor and lower after gemfibrozil treatment, although not significantly. We conclude that both Omacor and gemfibrozil have favorable effects on lipid and lipoprotein concentrations and the LDL subfraction profile. However, Omacor increased the susceptibility of LDL to oxidation, whereas gemfibrozil did not affect the resistance of LDL to oxidative modification in vitro. The clinical relevance of these changes remains to be established in the light of other postulated favorable effects of n-3 fatty acids on the course of cardiovascular disease.

Adult↗
PubMed1998

Effect of apolipoprotein E variants on lipolysis of very low density lipoproteins by heparan sulphate proteoglycan-bound lipoprotein lipase.

Lipoprotein lipase (LPL) is bound to heparan sulphate proteoglycans (HSPG) at the luminal surface of endothelium. It is the key enzyme involved in the hydrolysis of very low density lipoproteins (VLDL). Prior to lipolysis by LPL, the lipoproteins are considered to interact with vessel wall HSPG. Apolipoprotein (apo) E is thought to mediate this interaction thereby enhancing the stability of the lipoprotein-LPL complex. We hypothesize that apo E mutations may cause a diminished interaction of VLDL with HSPG leading to impaired lipolysis of VLDL by HSPG-bound LPL. In order to test this hypothesis, lipolysis experiments were performed using HSPG-bound LPL. The mean lipolysis rates of VLDL, isolated from the apo E2 (Lys146-->Gln) heterozygotes, apo E2 (Arg158-->Cys) homozygotes and apo E3-Leiden heterozygotes were 92.3 +/- 10.3 (ns), 77.3 +/- 4.2 (P < 0.05) and 76.7 +/- 10.0% (P < 0.05), respectively, of that of control VLDL (100.0 +/- 9.7%). No differences in lipolysis were observed between VLDL from controls and VLDL from the same patients if LPL in solution was used. Thus, compositional differences alone can not explain the differences in lipolysis rates observed with HSPG-bound LPL. In competition experiments, the binding efficiency to HSPG-LPL of VLDL from the apo E2 (Lys146-->Gln) heterozygotes, apo E2 (Arg158-->Cys) homozygotes and apo E3-Leiden heterozygotes was 63 (ns), 41 (P < 0.05) and 35% (P < 0.05), respectively of that of control VLDL (100%). We conclude that VLDL isolated from apo E2 homozygotes and apo E3-Leiden heterozygotes display decreased lipolysis by HSPG-bound LPL due to a defective binding of these lipoproteins to the HSPG-LPL complex.

Adult↗
PubMed1996

Lipoproteins, apolipoproteins, and low-density lipoprotein size among diabetics in the Framingham offspring study.

Diabetes mellitus has been shown to be associated with lipid abnormalities. Prior studies have indicated that women with diabetes have a risk of coronary heart disease similar to that of men. We compared lipid parameters in diabetic and nondiabetic participants in cycle 3 of the Framingham Offspring Study. Values for plasma total cholesterol (TC), triglyceride, lipoprotein, cholesterol, apolipoprotein (apo) A1, B, apo and lipoprotein(a) [Lp(a)] and low-density lipoprotein (LDL) particle size were analyzed in 174 diabetic and 3,757 nondiabetic subjects. Data from a total of 2,025 men and 2,042 women participating in the third examination (1983 to 1987) of the Framingham Offspring Study were subjected to statistical analysis. Male and female diabetics showed lower high-density lipoprotein (HDL) cholesterol, higher triglycerides, higher very-low-density lipoprotein (VLDL) cholesterol, lower apo A1, and higher LDL particle scores, indicating smaller size, than nondiabetics. Female diabetics also showed significantly higher TC and apo B values than nondiabetics. The results remained statistically significant after controlling for obesity and menopausal status. The presence of small dense LDL particles (pattern B) was highly associated with diabetes and hypertriglyceridemia in both sexes, and the relative odds for pattern B remained significant in women but not in men after adjustment for age and hypertriglyceridemia. No differences in apo E isoform distribution were found for diabetics and nondiabetics. Diabetes was not associated with elevated LDL cholesterol levels. In conclusion, diabetics have lower HDL cholesterol and higher triglyceride levels and are more likely to have small dense LDL particles. Diabetes is not a secondary cause of elevated LDL cholesterol. Lipid screening of diabetics should include full quantification of lipids for proper assessment of potential atherosclerotic risk.

Adult↗
PubMed1988

The effects of phthalimide and saccharin derivatives on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptor activity and related enzyme activities.

The hypolipidemic agents, phthalimide, saccharin, o-(N-phthalimido) acetophenone, N-(p-chlorobenzoyl) sulfamate, and o-chlorobenzylsulfonamide affected low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptor activity and lipoprotein degradation. In isolated rat hepatocytes, rat aorta foam cells, and human fibroblasts, LDL receptor activity, which is dependent on apo-B and -E, was inhibited by the drugs in a dose-dependent manner. LDL degradation was accelerated in the hepatocytes, while it was inhibited in aorta cells and fibroblasts. The drugs enhanced HDL receptor activity, dependent on apo-E and -A1, and HDL degradation in the hepatocytes, whereas in fibroblasts and aorta cells HDL receptor binding and degradation were suppressed. In parallel, activities of acyl CoA acyl transferase, sn-glycerol-3-phosphate acyl transferase, and heparin-induced lipoprotein lipase decreased and activities of HMG-CoA reductase and cholesterol oleate-ester hydrolase increased. In fibroblasts the presence of drugs enhanced HDL binding of intracellular cholesterol. In vivo studies demonstrated that phthalimide and saccharin treatment enhanced the clearance of HDL and decreased the clearance of LDL from the serum of rats. The results suggest that the mode of action of the agents is to modulate the lipoprotein receptor and, thereby, the clearance of lipids from peripheral tissue as part of the hypolipidemic activity.

Animals↗
PubMed2003

Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein.

LDL (low-density lipoprotein) is the major carrier of cholesterol in human plasma, and as such is intimately involved in the process of atherosclerosis. The lipoprotein class comprises a number of distinct subfractions, and is commonly divided into large, intermediate and small sized particles. Small, dense LDLs are held to be particularly atherogenic, since these particles are retained preferentially by the artery wall, are readily oxidized and carry an enzyme believed to have an important role in atherosclerosis, i.e. lipoprotein-associated phospholipase A(2). Generation of small, dense LDL occurs by intravascular lipoprotein remodelling as a result of disturbances such as Type II diabetes, metabolic syndrome, renal disease and pre-eclampsia. The key predisposing factor is the development of hypertriglyceridaemia, in particular elevation in the plasma concentration of large, triacylglycerol-rich VLDL (very-low-density lipoprotein). This leads to the formation of slowly metabolized LDL particles (5-day residence time), which are subject to exchange processes that remove cholesteryl ester from the particle core and replace it with triacylglycerol. LDL, so altered, is a potential substrate for hepatic lipase; if the activity of the enzyme is high enough, lipolysis will generate smaller, denser particles. Correction of the dyslipidaemia associated with small, dense LDL is possible using fibrates and statins, and this may contribute to the clinical benefits seen with these drugs. Fibrates act to lower plasma triacylglycerol (VLDL) levels, and so correct the underlying metabolic disturbance. Statins remove VLDL particles via receptor-mediated pathways and reduce the residence time (and hence limit the potential for remodelling) of LDL in the circulation.

Animals↗
PubMed1977

The passage of apoproteins from plasma lipoproteins into the lipoproteins of peripheral lymph in man.

1. The transport of apoprotein B from the lipoprotein of plasma into the lipoproteins of lymph draining the foot has been studied in four men with type III hyperlipoproteinaemia. 2. Three subjects were given autologous 125I-labelled very-low-density lipoprotein (VLDL) and 131I-labelled low-density lipoprotein (LDL) by intravenous injection; the fourth was given autologous 125I-labelled VLDL and 131I-labelled intermediate-density lipoprotein (IDL) plus LDL. 3. The 125I/131I ratios in serum and lymph apoprotein B, and the 125I and 131I specific radioactivities of apoprotein B in VLDL, IDL and LDL from serum and lymph, indicate that apoprotein B in the circulating VLDL can reach peripherallymph without the intermediacy of circulating LDL.

Adult↗
PubMed1999

Low density lipoprotein hemoperfusion by direct adsorption of lipoproteins from whole blood (DALI apheresis): clinical experience from a single center.

The elimination of low density lipoprotein (LDL) and lipoprotein (a) (Lp[a]) by conventional LDL apheresis techniques can only be achieved in a cell-free medium and thus requires the initial separation of plasma from the blood cells. The present paper describes the first LDL hemoperfusion system which is able to adsorb LDL and Lp(a) directly from whole blood. This simplifies the procedure substantially. The adsorber consists of polyacrylate ligands linked to a modified polyacrylamide matrix. These negatively charged polyacrylate ligands interact with the positively charged apoprotein B moiety of LDL and Lp(a), which results in selective adsorption of these lipoproteins onto the column. Three hypercholesterolemic patients suffering from overt atherosclerotic complications were treated weekly by direct adsorption of lipoproteins (DALI) (n = 20 sessions each). All patients were on the highest tolerated dose of cholesterol synthesis enzyme (CSE) inhibitors. About 1.3 patient blood volumes were treated per session. The anticoagulation was performed with acid citrate dextrose (ACD-A). The following acute reductions were achieved: LDL: 66%; Lp(a): 63%; and triglycerides: 29%. High density lipoprotein (HDL) (-13%) and fibrinogen (-16%) were not substantially reduced. The sessions were essentially uneventful. Due to a low ACD-A infusion rate, no hypocalcemic episodes were registered. One patient on enalapril was treated without complications when this angiotensin converting enzyme (ACE) inhibitor was withdrawn 2 days prior to apheresis. In summary, in our hands, DALI apheresis proved to be a simple, safe, and efficient method of lipid apheresis in hypercholesterolemic patients refractory to conservative lipid lowering therapy.

Adsorption↗
PubMed2000

Short and long-term effects of streptozotocin on dietary cholesterol absorption, plasma lipoproteins and liver lipoprotein receptors in RICO rats.

Adult male genetically hypercholesterolemic RICO rats were studied 6 and 28 days after streptozotocin (STZ) administration together with untreated RICO controls. The absorption coefficient of dietary cholesterol was determined using dual-isotope blood ratio method. Plasma lipoproteins as well as fecal neutral sterols and bile acids were analysed at both experimental times. Liver lipid parameters were measured and lipoprotein receptors (LDLr, SR-BI and HB2) were assayed by immunodetection. Six days after STZ administration, dietary cholesterol absorption was more efficient (+49%) in treated rats than in controls, and stayed higher (+68%) in the diabetic rats sacrificed at day 28. Fecal neutral sterol elimination decreased soon after STZ administration (by 35% at day 6), due to a higher cholesterol absorption coefficient, then increased to control level at day 28, due to installed diabetes-induced hyperphagia. Comparison of the lipoprotein profiles indicated that the concentration of HDL1. which is typically high in control Rico rats, fell significantly in diabetic rats at both experimental times, whereas that of HDL2 increased only at day 28. In diabetic rats, an early and strong enhancement of the hepatic expression of SR-BI appeared at day 6 (+415%) and persisted at day 28, but at a lesser extent (+85%). The expression of LDLr and HB2 was unchanged at day 6, but was significantly modified at day 28 (+140% for LDLr and -50% for HB2). These data show that streptozotocin-induced diabetes in Rico rats results in modifications of the expression of liver lipoprotein receptors which can contribute to alterations of the lipoprotein profile.

Animals↗
PubMed1992

Linkage of atherogenic lipoprotein phenotype to the low density lipoprotein receptor locus on the short arm of chromosome 19.

The atherogenic lipoprotein phenotype (ALP) is a common heritable trait characterized by a predominance of small, dense low density lipoprotein (LDL) particles (subclass pattern B), increased levels of triglyceride-rich lipoproteins, reductions in high density lipoprotein, and a 3-fold increased risk of myocardial infarction. Significant two-point linkage was found between ALP and the LDL receptor locus on the short arm of chromosome 19 in 51 relatives of nine probands with ALP pattern B. The maximum logarithm of odds (LOD) score of 4.07 was observed at a recombination fraction of 0.04, assuming 100% penetrance of ALP pattern B, and 4.27 at a recombination fraction of zero, assuming 90% penetrance of pattern B. Haplotyping data and multipoint linkage analysis suggest that the gene [named ATHS for atherosclerosis susceptibility (lipoprotein-associated)] responsible for ALP is located distal to D19S76 near or at the LDL receptor locus. This result suggests the possibility that genetic variation at the LDL receptor locus or a closely linked locus on chromosome 19 may be responsible for metabolic alterations in ALP pattern B that account for a substantial proportion of the familial predisposition to coronary artery disease in the general population.

Arteriosclerosis↗
PubMed1995

Analysis of ligand binding to the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Evidence that lipoprotein lipase and the carboxyl-terminal domain of the receptor-associated protein bind to the same site.

The endocytic alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2MR/LRP) binds several classes of extracellular ligands at independent sites. In addition, alpha 2MR/LRP can bind multiple copies of the 39-40-kDa receptor-associated protein (RAP). Both amino-terminal and carboxyl-terminal fragments of RAP exhibit affinity, and the fragments apparently bind to different sites on the receptor. RAP completely inhibits the binding of all presently known extracellular ligands, whereas several ligands such as alpha 2-macroglobulin and tissue-type plasminogen activator are poor inhibitors of RAP binding. Since RAP is largely an intracellular molecule that normally does not occupy alpha 2MR/LRP at the cell surface, we hypothesized that an established extracellular ligand might bind to those sites on the receptor capable of binding the RAP fragments. We found complete cross-competition between carboxyl-terminal RAP fragments and fragments of lipoprotein lipase containing the recently identified binding domain for alpha 2MR/LRP (Nykjaer, A., Nielsen, M., Lookene, A., Meyer, N., Røigaard, H., Etzerodt, M., Beisiegel, U., Olivecrona, G., and Gliemann, J. (1994) J. Biol. Chem. 269, 31747-31755). Moreover, the lipoprotein lipase fragment completely inhibited the binding of several alpha 2MR/LRP ligands in a pattern similar to that of carboxyl-terminal RAP fragments. On the other hand, the amino-terminal RAP fragment was a poor competitor of binding of the lipoprotein lipase fragment, whereas it competed effectively with pro-uPA for binding to the receptor. The results provide evidence that lipoprotein lipase binds to the site on alpha2MR/LRP also available for binding of the carboxyl-terminal domain of RAP and suggest that pro-uPA may bind to or overlap the site available for the amino-terminal domain of RAP.

Amino Acid Sequence↗
PubMed1997

Induced mutant mice expressing lipoprotein lipase exclusively in muscle have subnormal triglycerides yet reduced high density lipoprotein cholesterol levels in plasma.

To determine the contribution of muscle lipoprotein lipase (LPL) to lipoprotein metabolism, induced mutant mice were generated that express human LPL exclusively in muscle. By cross-breeding heterozygous LPL knockout mice with transgenic mice expressing human LPL only in muscle, animals were obtained that express human LPL primarily in skeletal muscle on either the null (L0-MCK) or normal (L2-MCK) LPL backgrounds, and these were compared with control littermates (L2). Fed and fasted post-heparin plasma (PHP) LPL activities were increased 1.4- and 2.3-fold, respectively, in L2-MCK mice and were normal in L0-MCK mice compared with controls. The specific enzyme activities of human LPL in mouse plasma was comparable to human LPL in human PHP. Skeletal muscle LPL activity was increased in both L2-MCK and L0-MCK mice in the fed (6.6-fold) and fasted (4.2-fold in L2-MCK; and 3.4-fold in L0-MCK) states. Adipose tissue LPL mRNA and activity were not detectable in L0-MCK mice. Growth and body mass composition were similar among all groups. In the fasted and fed state, L2-MCK mice had 31% and 53% reductions, respectively, in plasma triglycerides (TG), compatible with increased PHP LPL activity. Unexpectedly, both in the fasted and fed state the L0-MCK mice also had reduced TG (22%), despite normal PHP LPL activities. Very low density lipoprotein (VLDL) turnover studies revealed that the decreased TG were due to increased particle fractional catabolic rate in both L2-MCK and L0-MCK mice. Despite reduced TG, both L2-MCK and L0-MCK mice showed reduced high density lipoprotein (HDL) cholesterol levels (16% and 19%, respectively). HDL turnover studies indicated increased HDL cholesteryl ester fractional catabolic rate in the L2-MCK and L0-MCK compared with control mice. In summary, these studies suggest that muscle LPL is particularly potent with regard to VLDL metabolism and is sufficient to compensate for the lack of LPL in other tissues with regard to lipolyzing VLDL particles. With regard to HDL, muscle LPL expression does not result in normal levels due to enhanced breakdown either by mediating accelerated HDL clearance or by failing to establish normal HDL particles that are then cleared more quickly than normal. These studies provide new insights on the tissue-specific effects of LPL on lipoprotein metabolism.

Animals↗
PubMed2000

High affinity binding between lipoprotein lipase and lipoproteins involves multiple ionic and hydrophobic interactions, does not require enzyme activity, and is modulated by glycosaminoglycans.

Lipoprotein lipase (LPL) physically associates with lipoproteins and hydrolyzes triglycerides. To characterize the binding of LPL to lipoproteins, we studied the binding of low density lipoproteins (LDL), apolipoprotein (apo) B17, and various apoB-FLAG (DYKDDDDK octapeptide) chimeras to purified LPL. LDL bound to LPL with high affinity (K(d) values of 10(-12) m) similar to that observed for the binding of LDL to its receptors and 1D1, a monoclonal antibody to LDL, and was greater than its affinity for microsomal triglyceride transfer protein. LDL-LPL binding was sensitive to both salt and detergents, indicating the involvement of both hydrophobic and hydrophilic interactions. In contrast, the N-terminal 17% of apoB interacted with LPL mainly via ionic interactions. Binding of various apoB fusion peptides suggested that LPL bound to apoB at multiple sites within apoB17. Tetrahydrolipstatin, a potent enzyme activity inhibitor, had no effect on apoB-LPL binding, indicating that the enzyme activity was not required for apoB binding. LDL-LPL binding was inhibited by monoclonal antibodies that recognize amino acids 380-410 in the C-terminal region of LPL, a region also shown to interact with heparin and LDL receptor-related protein. The LDL-LPL binding was also inhibited by glycosaminoglycans (GAGs); heparin inhibited the interactions by approximately 50% and removal of trace amounts of heparin from LPL preparations increased LDL binding. Thus, we conclude that the high affinity binding between LPL and lipoproteins involves multiple ionic and hydrophobic interactions, does not require enzyme activity and is modulated by GAGs. It is proposed that LPL contains a surface exposed positively charged amino acid cluster that may be important for various physiological interactions of LPL with different biologically important molecules. Moreover, we postulate that by binding to this cluster, GAGs modulate the association between LDL and LPL and the in vivo metabolism of LPL.

Animals↗