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PubMed2000

Lipoprotein lipase activity is associated with severity of angina pectoris. REGRESS Study Group.

BACKGROUND: Raised triglyceride-rich lipoproteins significantly increase the risk for cardiovascular disease. Variation in the activity of the enzyme lipoprotein lipase (LPL), which is crucial in the removal of these lipoproteins, may therefore modulate this risk. METHODS AND RESULTS: Postheparin levels of LPL activity and mass were measured in a large cohort of male coronary artery disease patients participating in the Regression Growth Evaluation Statin Study (REGRESS), a lipid-lowering regression trial. In addition, the relationships between LPL activity and mass and severity of angina pectoris according to the NYHA classification and silent ischemia on 24-hour ambulatory ECG monitoring were assessed. Patients in different LPL activity quartiles and mass had different severities of angina; a total of 47% of patients in the lowest LPL quartile reported class III or IV angina. In contrast, only 29% in the highest activity quartile (P:=0.002) had severe angina. These parameters were supported by ambulatory ECG results, for which the total ischemic burden in the lowest LPL activity quartile was 36. 5+/-104.1 mm x min compared with 14.8+/-38.8 mm x min in the highest quartile of LPL activity (P:=0.001). LPL activity levels were strongly correlated with LPL mass (r=0.70, P:<0.0001). A significant association between the LPL protein mass and NYHA class (P:=0.012) was also demonstrated. CONCLUSIONS: We have demonstrated a significant relationship between LPL mass and activity and severity of ischemia as defined by angina class and ambulatory ECG. These results suggest that LPL influences risk for coronary artery disease by both catalytic and noncatalytic mechanisms.

Aged↗
PubMed1996

Human lipoprotein lipase deficiency: does chronic dyslipidemia lead to increased oxidative stress and mitochondrial DNA damage in blood cells?

Lipoprotein lipase (LPL) is a key enzyme in the metabolism of lipoproteins and their balanced distribution in the plasma. A deficiency of this enzyme due to gene mutations leads to severe dyslipidemia. In this report, we describe the major LPL gene mutations that are prevalent in the French-Canadian population of Québec and the nature of dyslipidemia caused by the resulting enzyme deficiency. We discuss the possibility that dyslipidemia caused by LPL deficiency may enhance oxidative stress in the blood cells, bring about increased fluidity of the membrane components of these cells and increase the susceptibility of their mitochondrial DNA to structural alterations. Some preliminary experimental results in verification of this hypothesis are presented.

Animals↗
PubMedDate not supplied

In vivo and in vitro release of lipoprotein lipase and hepatic lipase by low molecular weight heparins.

The purpose of this study was to compare lipoprotein lipase (LPL) and hepatic lipase (HL) releasing activities of different low molecular weight heparins (LMWH) and of a standard heparin. In vivo, the injection of most LMWH led to a LPL and HL releasing activity inferior to that obtained with a standard heparin. The releasing of LPL by muscle in vitro and of HL by perfused liver was identical with both types of heparins, but in epididymal adipose tissue, LPL activity released by LMWH was generally higher than the activity released by unfractionated heparin. We have no explanation for this apparent contradiction between the in vivo and in vitro results.

Adipose Tissue↗
PubMed1981

Redistribution of apolipoproteins C removed from human very low density lipoprotein during in vitro lipolysis by lipoprotein lipase.

In order to localize the labelled apolipoproteins C removed from Very Low Density Lipoproteins (VLDL) during lipolysis by lipoprotein lipase, we used human VLDL labelled with 125I-labelled apolipoproteins C and employed density gradient ultracentrifugation to analyze lipolytic products. Triacylglycerol hydrolysis occurs when albumin is present even in the absence of serum or High Density Lipoproteins (HDL). In this case, apolipoproteins C were found to be located in several fractions, in different density regions. When either HDL or serum were present in the incubation medium, the removed apolipoproteins C were recovered in only one main fraction in the high density region (1.10 g/ml). Incubations in the presence of either HDL2 or HDL3 gave quite similar results.

Apolipoproteins↗
PubMed2001

Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance.

Lipoprotein lipase (LPL) plays a rate-limiting role in triglyceride-rich lipoprotein metabolism and is expressed in most tissues. Overexpression of LPL in skeletal muscle has been linked with higher plasma glucose levels suggesting insulin resistance (Jensen et al., Am J Physiol 273:R683-R689, 1997). The aim of our study was to ascertain whether the overexpression of human LPL in skeletal muscle leads to insulin resistance and to investigate the mechanism. Respiratory quotient measurements in both transgenic (MCKhLPL) and nontransgenic mice on a high-carbohydrate diet were conducted and showed a shift in fuel usage in transgenic mice when fasting but not when actively feeding. An increase in citrate and glucose 6-phosphate levels in fasted MCKhLPL mice further supports this preferential use of lipids. When challenged with an intraperitoneal injection of glucose (1 g/kg), MCKhLPL mice had a higher plasma glycemic excursion than nontransgenic mice. No differences in insulin response were observed between the two groups. Further investigation using hyperinsulinemic-euglycemic clamps revealed insulin resistance in MCKhLPL mice. Despite signs of insulin resistance, there was no associated increase in free fatty acids, hypertriglyceridemia, or hyperinsulinemia in MCKhLPL mice. In conclusion, MCKhLPL mice are insulin resistant, presumably due to increased delivery of lipoprotein-derived fatty acids to muscle.

Animals↗
PubMed1994

Lipoprotein lipase activity in patients with combined hyperlipidaemia.

The aetiology of familial combined hyperlipidaemia remains obscure, with both genetic and environmental factors contributing to the phenotype, which is frequently associated with premature coronary heart disease. We have studied lipoprotein lipase (LPL) activity and hepatic lipase (HL) activity in patients with coronary heart disease to determine whether variation in lipase activities contributes to this phenotype. Forty-one patients (mean age 50 years; 30 male) were selected on the basis of cholesterol levels above 6.5 mmol/l and triglyceride levels above 2.2 mmol/l, with apoprotein B values over the 90th percentile. There was a family history of premature coronary heart disease in 78% and a personal history in 64%, at mean age 44, the patient group therefore predominantly corresponded to the common definition of familial combined hyperlipidaemia, appropriate in the absence of molecular markers. None of the patients was diabetic; hypertension and smoking were not over represented. Blood samples were taken following intravenous administration of heparin (100 IU/kg body wt), and LPL and HL activities were measured. Mean post-heparin LPL was significantly lower in patients than controls 10 min after heparin administration (2.98 +/- 1.04 and 3.86 +/- 0.93 mumol ml-1 h-1, respectively, P = 0.001), and 37% patients had values below the 10th percentile of controls. Both male and female patients had significantly higher HL activities than their respective controls at 5, 10, 20 and 30 minutes post-heparin. As expected, both female patients and controls had lower HL activities than males, although this sex difference did not reach statistical significance in the patient group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1980

Mechanism of action of milk lipoprotein lipase at substrate interfaces: effects of apolipoproteins.

The mechanism of action of bovine milk lipoprotein lipase was studied by using a monomolecular film of 1,2-didecanoylglycerol. The apparent rate of hydrolysis of diglyceride increased with increasing surface pressures above 12 mN/m; the enzyme was inactive at pressures less than 12 mN/m. We have measured the effects of four plasma apolipoproteins (apoC-II, apoC-III, apo-I, and apoE), bovine serum albumin, porcine pancreatic colipase, heparin, and NaCl on the kinetics of lipid hydrolysis. At a surface pressure of 15 mN/m, all of the proteins, with the exception of colipase, gave increased enzyme activity compared to lipase alone; apoC-II gave maximal activation. At 25 mN/m, apoC-II at concentrations of less than 0.25 microgram/mL showed a specific activation, whereas the other proteins had no effect. Heparin activated at both high and low surface pressures; NaCl had little or no effect in this system. At a higher concentration of apoC-II (0.50 microgram/mL), the apoprotein inhibited the enzyme. The addition of apoC-III, apoA-I, or apoE (final concentration 0.25 microgram/mL), but not albumin or colipase, to apoC-II (0.25 microgram/mL) caused an increase in surface pressure of 5-6 mN/m and an apparent rate which was less than half that found for lipase alone, suggesting that all of the apoproteins inhibit the apoC-II specific activation.

Animals↗
PubMed1994

Binding of lipoprotein lipase to alpha 2-macroglobulin.

The interaction between bovine lipoprotein lipase (bLPL) and human alpha 2-macroglobulin (alpha 2M) was studied by use of non-denaturing PAGE and gel-permeation, Zn(2+)-Sepharose and heparin-Sepharose chromatography. It was demonstrated that bLPL in vitro binds non-covalently to native alpha 2M, but not to the receptor-recognized form produced by treatment of alpha 2M with chymotrypsin or methylamine. A small amount of bLPL was bound covalently to alpha 2M by disulphide interchange, when incubated together with chymotrypsin or methylamine. Whereas alpha 2M in complex with bLPL still bound to Zn(2+)-Sepharose, bLPL lost the ability to bind to heparin-Sepharose. Preincubation of bLPL with heparin prevented complex-formation with alpha 2M, suggesting that alpha 2M interacts with the heparin-binding domain of bLPL. Experiments in which 125I-bLPL was incubated with human plasma at 20 degrees C demonstrated an 11-17% binding of the labelled lipase to alpha 2M, indicating that this interaction may be of physiological significance.

Animals↗
PubMed1995

Overexpression of human lipoprotein lipase protects diabetic transgenic mice from diabetic hypertriglyceridemia and hypercholesterolemia.

We investigated the role of the overexpression of lipoprotein lipase (LPL) in lipoprotein abnormalities in transgenic mice with streptozotocin-induced diabetes mellitus. Before the induction of diabetes, LPL activity was 4.6-fold in skeletal muscle and 2.0-fold higher in the heart in transgenic mice than in their nontransgenic littermates. LPL activity in skeletal muscles in diabetic nontransgenic mice and cardiac LPL activity in diabetic nontransgenic and transgenic mice were decreased. Body weights were similarly reduced, and no appreciable amount of adipose tissue was observed in diabetes in both groups. The plasma triglyceride level was lower in diabetic transgenic mice than in diabetic nontransgenic mice (33.2 +/- 22.5 versus 185.3 +/- 57.4 mg/dL). Induction of diabetes was associated with a significant increase in the plasma cholesterol level in nontransgenic mice (90.0 +/- 11.1 versus 163.9 +/- 39.3 mg/dL) but much less in transgenic mice. Our results indicate that overexpression of LPL in transgenic mice inhibited diabetes-associated hypertriglyceridemia and hypercholesterolemia but did not affect the loss of body weight induced by diabetes.

Animals↗
PubMed1984

Lipoprotein lipase is produced, regulated, and functional in rat brain.

Lipoprotein lipase (LP lipase, triacylglycero-protein acylhydrolase EC 3.1.1.34) activity was found in four dissimilar brain regions (hypothalamus, cortex, cerebellum, and midbrain) of adult male rats. Progressive accumulation of LP lipase activity in cultured fetal rat hypothalamic cells was also observed, indicating de novo synthesis of the lipase. The brain LP lipase activity was serum-dependent and was inhibited by 1 M NaCl and by protamine sulfate. Kinetic analysis revealed an apparent Km of 0.79 mM very similar to that of rat adipose tissue LP lipase. That the lipase was functioning in the cultured brain cells was indicated by uptake and incorporation of radioactivity from tri[( 1-14C]oleoyl)glycerol into cellular triacylglycerols, and into more polar lipids, such as phosphatidylcholine. Furthermore, brain LP lipase activity in adult rats was decreased in all four regions examined, most significantly in the hypothalamus, after 72 hr of food deprivation. Thus, authentic LP lipase is present in adult rat brain and can be synthesized by isolated brain cells in vitro. LP lipase also mediates the uptake of triacylglycerol fatty acids and their subsequent incorporation into cellular lipids of cultured brain cells. Decreased brain LP lipase activity after fasting suggests that this enzyme may be regulated by metabolic or nutritional factors. Because the largest changes in LP lipase activity in response to food deprivation occurred in the hypothalamus, the enzyme may have a role in hypothalamic control of food intake or in body-weight regulation.

Animals↗
PubMed1976

Very low density lipoprotein. Dissociation of apolipoprotein C during lipoprotein lipase induced lipolysis.

The fate of apo C in rat plasma very low density lipoprotein (VLDL) during lipolysis was studied using VLDL labeled specifically with 125I-labeled apo C and purified bovine milk lipoprotein lipase. Incubations were carried out in vitro and included serum-containing systems and albumin containing systems. Free fatty acids generation proceeded with time of incubation in the two systems. It, however, was enhanced 1.5--2 fold by the presence of serum. 125I-labeled apo C equilibrated between very low and high density lipoprotein (HDL) in both systems even when enzyme was not present in the incubation medium, or when the incubation was carried out at 0 degrees C. Upon initiation of lipolysis, more 125I-labeled apo C was transferred to HDL and the transfer was proportional to the magnitude of free fatty acids release. 125I-labeled apo C was also progressively removed from VLDL in the albumin-containing system, although no known lipoprotein acceptor to apo C was present in the medium. The 125I-labeled apo C was recovered predominantly with the medium fraction of d greater than 1.21 g/ml (60--70%), and to a lesser degree with that of d= 1.019--1.21 g/ml. However, the relationship between lipolysis (measured as free fatty acids release) and removal of 125I-labeled apo C from VLDL were indistinguinshable in the albumin containing system and the serum containing system. On the basis of these observations, it is postulated that the removal of apo C during lipolysis of VLDL reflects the nature of the partially degraded VLDL particles, and is independent of the presence of a lipoprotein acceptor to apo C.

Albumins↗
PubMed1996

Heparan sulfate-dependent and low density lipoprotein receptor-related protein-dependent catabolic pathways for lipoprotein lipase in mouse embryonic fibroblasts.

Heparan sulfate and low density lipoprotein receptor related protein (LRP) have been shown to participate in the uptake and degradation of the enzyme lipoprotein lipase (LPL). Yet, the contribution of each of these pathways to LPL metabolism and their possible dependence is unknown. In the present study we examined the metabolism of 125I-labeled LPL in untreated and heparinase-treated primary wild-type mouse embryonic fibroblasts (MEF) and in mouse fibroblasts that express single LRP allele (PEA-10) or are lacking the LRP (PEA-13). The degradation of LPL in PEA-13 cells was 30% lower than in MEF and PEA-10 cells. Heparinase treatment decreased the LPL degradation by 58%, 79% and 92%, whereas heparin reduced such degradation by 87%, 90% and 94% in MEF, PEA-10 and PEA-13 cultures, respectively. Assuming that a) heparinase treatment abolished the heparan-sulfate pathway, and that b) the degradation remaining in heparin-treated cultures represents nonspecific values, it appears that heparan sulfate contributes about 61%, 83% and 95% of total LPL degradation, whereas the LRP pathway contributes 39%, 17% and less than 5% of LPL degradation in MEF, PEA-10 and PEA-13 cells, respectively. In addition, the data indicate that LPL interaction with heparan sulfate and the LRP pathways is independent of each other. The study shows that these cells possess both a heparan sulfate-dependent pathway and an LRP-dependent pathway for LPL metabolism and that the two pathways are independent of each other.

Alleles↗
PubMed1989

Structure of the human lipoprotein lipase gene.

Human genomic clones that span the entire lipoprotein lipase (LPL) gene have been isolated and used to determine its structure. The gene is approximately 30 kilobase (kb) pairs in length in which the mRNA specifying sequence is divided into 10 exons. Exons 1-9 are of average size (105-276 bp) whereas exon 10, which specifies the entire 3' uncoding sequence, is 1948 bp in length. Exon 1 codes for the signal peptide, exon 2 includes the protein domain that was shown to bind to the lipoprotein substrate, and exons 6 and 9 code for sequences that are relatively rich in basic amino acids and therefore likely to be involved in anchoring of the enzyme to the capillary endothelium by interaction with the acidic domain of heparan sulfate. Four closely spaced mRNA 5' termini were observed, indicating multiple transcription initiation sites, one of which seems to be favored. Two potential enhancer sequence motifs in the 5' upstream region were observed. One may specify expression in response to intracellular Ca2+ mobilization, and the other may be responsible for expression in adipocytes.

Base Sequence↗
PubMed1981

Characterization of glycosaminoglycans in urine from patients with nephrotic syndrome and control subjects, and their effects on lipoprotein lipase.

Previously we found that alpha 2-acid glycoprotein fraction from urine of patients with the nephrotic syndrome stimulated the lipoprotein lipase reaction in vivo and in vitro. The activator was separated from the alpha 1-acid glycoprotein and identified as a glycosaminoglycan. The studies reported here were undertaken to characterize and quantify the glycosaminoglycans contained in urine of patients with the nephrotic syndrome and to compare these to the glycosaminoglycans in urine of the control subjects. We found that free low molecular weight glycosaminoglycans, heparan sulfate and chondroitin 4-sulfate, are excreted in both patients with the nephrotic syndrome and controls however, patients with the nephrotic syndrome excreted much less of both glycosaminoglycans. The free form of heparan sulfate was found to be the activator which stimulated the lipoprotein lipase reaction in vitro in the presence of apolipoprotein CII. In addition, the urine from patients with the nephrotic syndrome contained a protein-glycosaminoglycan complex which was absent in control urine. Glycosaminoglycans in the complex could be released by papain digestion or by trichloroacetic acid. Our evidence indicates that this glycosaminoglycans fraction is a law charge form of chondroitin sulfate.

Chondroitin Sulfates↗
PubMed1985

Non-response of muscle capillary density and lipoprotein-lipase activity to regular training in diabetic patients.

Ten obese women with normal glucose tolerance, 10 obese patients with sulphonylurea-treated non-insulin-dependent diabetes (NIDD) and 11 patients with insulin-dependent diabetes (IDD; treated for 3-31 yr) took part in a 10-week programme of physical training in 50-min sessions, 2-3 times a week. As a result of training, maximal oxygen uptake increased significantly by about 18, 13 and 8% in the 3 groups, respectively, and citrate synthase in muscle increased significantly by 27-42%. The lipoprotein-lipase activity in muscle tissue (sampled by a needle-biopsy technique from the lateral vastus muscle) did not change. The number of capillaries/fibre in muscle tissue increased. This was accompanied by an increase in muscle fibre area, resulting in an unchanged number of capillaries/mm2. This may explain why the lipoprotein-lipase activity was unaltered. The latter activity in the group with IDD was lower than was predicted from the number of capillaries/mm2. This number was in fact larger than in the obese and NIDD groups. These results indicate that the increase in capillary density and lipoprotein-lipase activity that occurs in healthy young individuals as an effect of endurance training does not take place in obese, NIDD and IDD patients.

Adult↗
PubMed1983

A comparison of the lipoprotein lipase activity in the tissues and post-heparin plasma of atherosclerosis-susceptible and atherosclerosis-resistant pigeons.

1. The lipoprotein lipase activity measured in acetone-ether powders of tissues from White Carneau and Show Racer pigeons was invariably somewhat lower in the former compared with the latter species. 2. At 100 and 200 Units of heparin per kg body weight the peak post-heparin lipolytic activity present in the plasma of White Carneau pigeons was significantly lower than that for Show Racers. At 50 Units per kg, this position was reversed. 3. It was concluded that the White Carneau pigeon may have an impaired functional lipoprotein lipase capacity compared to the Show Racer control.

Adipose Tissue↗
PubMed2003

The lipoprotein lipase Ser447Ter mutation and risk of stroke in the Chinese.

BACKGROUND: Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism. The Ser447Ter mutation of LPL may be associated with ischemic cerebrovascular diseases. We investigated whether the LPL variants were related to risk of strokes in Chinese Hans. METHODS: We recruited 160 patients with cerebrovascular diseases (ischemic stroke, n=96; hemorrhagic stroke, n=64) and 117 age-matched controls. All subjects were Chinese Hans. Subjects were analyzed for the Ser447Ter mutation by restriction fragment length polymorphisms of the LPL gene. RESULTS: As compared with controls, the frequency of LPL genotype CG (heterozygous Ser447Ter mutation) was lower in ischemic stroke patients (10.4% vs. 21.4%, p<0.05), and was not significantly different in hemorrhagic stroke patients (15.6% vs. 21.4%, p>0.05). The LPL G allele frequency was also lower in ischemic stroke patients (5.2%) vs. controls (10.7%, p<0.05). There was no difference between hemorrhagic stroke patients (7.8%) and controls. Serum Lp(a) concentrations were markedly lower in CG carriers than that in CC carriers in both stroke patients and the controls (p<0.05). There was no significant difference in the concentrations of other lipids. CONCLUSIONS: Patients with ischemic stroke have a lower frequency of the LPL Ser447Ter mutation, which indicates that this mutation may have protective effect on ischemic stroke.

Aged↗
PubMed2000

Associations between lipoprotein lipase gene polymorphisms and insulin resistance in coronary heart disease.

BACKGROUND: Lipoprotein lipase (LPL) is a crucial enzyme in plasma lipoprotein metabolism. Variants of the LPL gene (Pvu II and Hind III polymorphisms) may increase the risk of developing coronary heart disease (CHD) but their effect on insulin resistance remains unknown. The present study was conducted to examine whether DNA variations of the LPL gene were related to insulin resistance, carbohydrate and lipid risk factors for CHD in nondiabetic individuals. METHODS: Pvu II and Hind III allele status of the LPL gene and fasting plasma glucose, insulin and lipid values were determined in nondiabetic men with angiographically documented CHD (n = 102) and in a control group (n = 145). Plasma glucose and insulin responses to a 75-g oral glucose tolerance test and insulin resistance as measured by an insulin suppression test were also carried out in 46 (45%) of the patients with CHD and in 73 (50%) of the control individuals. RESULTS: The allele frequencies of LPL Pvu II and Hind III were not significantly different between the CHD patients and the controls. No association was found between Pvu II status and blood pressure, fasting plasma glucose, insulin, lipid levels or insulin resistance in patients with CHD. Nevertheless, compared with individuals with the Hind III H2H2 allele, CHD patients carrying the H1 allele (H1H1 + H1H2) were more insulin resistant, as indicated by higher steady state plasma glucose concentrations (253 +/- 87 vs 200 +/- 74 mg/dl, p = 0.032). CONCLUSIONS: We suggest that the LPL gene Hind III allele might be associated with insulin resistance in nondiabetic men with CHD. However, further studies with larger populations of both sexes will be required to confirm this finding.

Adult↗