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PubMed1991

DNA polymorphism haplotypes of the human lipoprotein lipase gene: possible association with high density lipoprotein levels.

Lipoprotein lipase (LPL) plays a central role in the metabolism of lipoproteins by hydrolyzing the core triglycerides of circulating very low density lipoproteins and chylomicrons. The enzyme is encoded by a gene about 30 kb in size located on the short arm of human chromosome 8. We have determined the locations of the four common DNA polymorphisms along the gene, including a polymorphism that occurred only among an American black population examined. These restriction site polymorphisms were used for haplotype analysis of Mediterranean and US black families. Estimation of the extent of nonrandom association between these polymorphisms indicated considerable linkage disequilibrium between these sites. No correlation was observed between the level of linkage disequilibrium and the physical distance of the polymorphic sites. The polymorphism information content of the haplotypes ranged from 0.65 to 0.74, thereby constituting a relatively useful genetic marker on chromosome 8. We tested for possible associations between the polymorphisms and circulating lipoprotein phenotypes in a population of 139 Caucasians undergoing coronary arteriography and 50 of their spouses. Some possibly significant associations between LPL gene polymorphisms and levels of high density lipoprotein cholesterol (P = 0.015) and total plasma cholesterol (P = 0.025) were observed. In contrast to a previous report, we found no significant associations with the levels of plasma triglycerides.

Adult↗
PubMed1999

Lipoprotein lipase greatly enhances the retention of lipoprotein(a) to endothelial cell-matrix.

The trapping of apolipoprotein (apo)B containing lipoproteins within the arterial subendothelial matrix (ECM) is an early event in atherosclerosis. When lipoprotein lipase, a constituent of the ECM, is prebound to ECM both LDL and oxidized LDL binding is greatly enhanced. In this study we compared the binding of lipoprotein(a) (Lp(a)), a lipoprotein correlated with atherosclerosis and restenosis, to ECM in the presence of varying concentrations of LPL. Without LPL, Lp(a) binding was low and non-saturable. In the presence of LPL, Lp(a) retention increased from 2.7 x 10(-7) to 1.13 x 10(-4) nmoles. Scatchard analysis demonstrated that the affinities of both Lp(a) and LDL to lipase were similar. In competition experiments, LDL, apoE, polymers of lysine and arginine were all capable of preventing the lipase specific [125I]Lp(a) retention. However, neither collagen nor fibronectin were capable of blocking or displacing [125I]Lp(a) from the lipase bound to ECM. In a separate set of experiments, when ECM was not saturated with lipase, both fibronectin and collagen (at 10-fold protein excess) prevented approximately 40% of total [125I]Lp(a) retention to ECM. These data suggest, in the absence of lipase, apo(a) may regulate the binding of Lp(a) to ECM. Whereas, lipase enhanced the binding of Lp(a) to ECM, most probably through the apoB moiety of the Lp(a) particle.

Animals↗
PubMed1995

Structural features in lipoprotein lipase necessary for the mediation of lipoprotein uptake into cells.

Lipoprotein lipase (LpL) has been shown to mediate the uptake of lipoproteins into cells. The uptake is initiated by binding of LpL to cell surface proteoglycans and to the low density lipoprotein (LDL) receptor-related protein. This ability of LpL is independent of catalytic activity and depends on the intact dimeric structure of the lipase and functional residues in the C-terminal domain. The goal of this study was to identify structural features in LpL that are essential in the mediation of lipoprotein uptake. Naturally occurring variants and LpL mutants produced by site-directed mutagenesis were cloned and expressed in COS-cells. A combination of immunoassays and separation on heparin-Sepharose columns was used to determine the molar ratio of monomeric to dimeric LpL in the expression media. The mutants were tested for their ability to mediate the uptake of 125I-labeled beta-VLDL in cultured Hep3b cells in direct comparison with wild type LpL. We found that the concentration of monomer in the media correlated negatively with the effect on the uptake mediated by the dimeric form of LpL. A mutation affecting the catalytic activity (Asp 156Gly) resulted in no significant reduction in the lipase-mediated beta-VLDL uptake. Point mutations in the proposed lipid binding region Trp390Ala or Trp393Ala and the substitution of 390-393 with the homologous hepatic lipase (HL) sequence were also normal, while the deletion of 390-393 reduced the ability to mediate the uptake by about 60% in comparison to wild type. A mutation known to impair heparin binding (Arg294Ala) was also less efficient than the wild type in mediating uptake. In conclusion, it is important to determine the monomer/dimer ratio in mutant preparations as the presence of monomers inhibits the uptake mediated by the dimeric LpL. Moreover, sites involved in heparin and lipid binding between residues 390-421 are important for LpL-mediated lipoprotein uptake.

Catalysis↗
PubMed1992

Alterations in erythrocyte membrane lipid composition and fluidity in primary lipoprotein lipase deficiency.

Lipid composition of plasma lipoproteins and erythrocyte ghost membranes has been studied in 16 healthy normolipidaemic subjects and in 16 patients affected by primary lipoprotein lipase deficiency, resulting in severe chylomicronaemia and in cholesterol-depleted low-density lipoproteins and high-density lipoproteins. A significant decrease in membrane cholesterol/phospholipid ratio was observed in lipoprotein lipase deficient patients compared to controls (3.27 +/- 0.33 vs. 3.95 +/- 0.50, mean +/- S.D.; P less than 0.0001). There was also an increase in the erythrocyte membrane phosphatidylcholine/sphingomyelin ratio in lipoprotein lipase deficient patients compared to controls (1.53 +/- 0.10 vs. 1.05 +/- 0.13; P less than 0.0001) due to a concurrent increase in phosphatidylcholine and decrease in sphingomyelin relative concentrations in these patients. Erythrocyte ghost membrane fluidity was determined by fluorescence anisotropy and found to be higher in membranes from lipoprotein lipase deficient patients. This increase in membrane fluidity can be attributed in part to changes in membrane cholesterol and phospholipid concentrations in response to abnormal plasma lipoprotein composition.

Adolescent↗
PubMed1978

Comparison of the phospholipase activity of bovine milk lipoprotein lipase against rat plasma very low density and high density lipoprotein.

The hydrolytic activity of a lipoprotein lipase from bovine milk against triacylglycerol and phosphatidylcholine of rat plasma very low density lipoprotein was determined and compared to that against phosphatidylcholine of high density lipoprotein. 85--90% of the triacylglycerol in very low density lipoprotein were hydrolyzed to fatty acids and 25--35% of the phosphatidylcholine to lysophosphatidylcholine. High density lipoprotein phosphatidylcholine was only minimally susceptible to the enzyme. Even with high amounts of enzyme and prolonged incubation periods, lysophosphatidylcholine generation did not exceed 2--4% of the original amounts of labeled phosphatidylcholine in the high density lipoprotein. We conclude that phospholipids in high density lipoprotein are not substrates for the phospholipase activity of this lipoprotein lipase. These observations suggest that factors other than the presence of apolipoprotein C-II and of glycerophosphatides are of importance for the activity of lipoprotein lipases.

Animals↗
PubMed1976

The inhibition in vivo of lipoprotein lipase (clearing-factor lipase) activity by triton WR-1339.

1. Lipoprotein lipase activity was measured in heart homogenates and in heparin-releasable and non-releasable fractions of isolated perfused rat hearts, after the intravenous injection of Triton WR-1339. 2. In homogenates of hearts from starved, rats, lipoprotein lipase activity was significantly inhibited (P less than 0.001) 2h after the injection of Triton. This inhibition was restricted exclusively to the heparin-releasable fraction. Maximum inhibition occurred 30 min after the injection and corresponded to about 60% of the lipoprotein lipase activity that could be released from the heart during 30 s perfusion with heparin. 3. Hearts of Triton-treated starved rats were unable to take up and utilize 14C-labelled chylomicron triacylglycerol fatty acids, even though about 40% of heparin-releasable activity remained in the hearts. 4. It is concluded that Triton selectively inhibits the functional lipoprotein lipase, i.e. the enzyme directly involved in the hydrolysis of circulating plasma triacylglycerols. 5. Lipoprotein lipase activities measured in homogenates of soleus muscle of starved rats and adipose tissue of fed rats were decreased by 25 and 39% respectively after Triton injection. It is concluded that, by analogy with the heart, these Triton-inhibitable activities correspond to the functional lipoprotein lipase.

Adipose Tissue↗
PubMed1985

Antibody against rat adipose tissue lipoprotein lipase.

To facilitate detailed studies of rat adipose tissue lipoprotein lipase regulation, a high titre polyclonal antibody was raised against purified rat adipose tissue lipoprotein lipase (in a goat). The first stage of the purification of the lipoprotein lipase was carried out with heparin-Sepharose affinity chromatography. In the second stage we took advantage of the binding property of lipoprotein lipase to ampholytes. These ampholytes, used during this second step, do not have to be eliminated prior to injecting the enzyme preparation into the animal. They have neither toxic nor antigenic effects on the animal; moreover, their presence does not affect the antigenic potency of the lipoprotein lipase. When pre-incubated with a constant amount of adipose tissue lipoprotein lipase (8 mU/75 microliter), an equal volume of the antiserum raised either pure or diluted up to 1/50 resulted in complete inhibition of enzyme activity, and half maximal inhibition was observed at a dilution of 1/800. The antibody was effective in inhibiting rat heart lipoprotein lipase but not salt-resistant hepatic lipase. Immunodiffusion revealed a single line of precipitation between this antibody and the adipose tissue lipoprotein lipase.

Adipose Tissue↗
PubMed1978

Regulation of lipoprotein lipase immunological study of adipose tissue.

An antibody to purified rat heart lipoprotein lipase was used to determine the relative specific activities of adipose tissue lipoprotein lipase from fed and fasted rats. The antibody was immobilized by coupling it to a Sepharose gel. This antibody bound approx. 80% of the lipoprotein lipase activity of extracts of rat adipose tissue. When the extracts were separated by gel chromatography into two lipase activity fractions (lipoprotein lipase "a" and lipoprotein lipase "b") and these fractions incubated with the antibody, only 10% of the lipoprotein lipase "a" activity was bound by the highest antibody concentration employed, whereas 93% of the lipoprotein lipase "b" was bound by the same amount of antibody. Increasing amounts of antibody incubated with extracts of adipose tissue of fed or fasted rats yielded similar titration curves. When a constant amount of antibody was incubated with increasing amounts of the adipose extracts, no significant difference was noted between extracts from fed and fasted animals. The data indicate that the high lipoprotein lipase activity of adipose tissue of fed rats, compared with that of rats fasted overnight, results from the presence of more lipoprotein lipase protein.

Adipose Tissue↗
PubMed1986

Intracellular localization of lipoprotein lipase in adipose cells.

Subcellular localization of lipoprotein lipase has been examined in differentiated Ob17 adipose cells. No patent activity is detectable in carefully homogenized cells. All latent activity can be unmasked by disrupting membrane structures with neutral detergents. The sequestration of lipoprotein lipase in closed membrane structures is supported by experiments of immunotitration with anti-lipoprotein lipase antibodies and by experiments showing a full protection of the masked activity against proteolytic attack by trypsin. The intracellular distribution of lipoprotein lipase investigated by immunofluorescence staining and by isopycnic centrifugation indicates that a large proportion of the enzyme is located in the Golgi apparatus, in which the activation of the enzyme is likely to take place (C. Vannier et al. (1985) J. Biol. Chem. 260, 4424-4431). Altogether, the results are in favor of a localization of lipoprotein lipase in adipose cells as being typical of that of a secretory protein and underline the absence of lipoprotein lipase in the cell cytoplasm.

Adipose Tissue↗
PubMed2003

Deficiency of choresteryl ester transfer protein and gene polymorphisms of lipoprotein lipase and hepatic lipase are not associated with longevity.

Cholesteryl ester transfer protein (CETP) is one of the key proteins in reverse cholesterol transport (RCT). The role of CETP in atherosclerosis remains controversial. In this study we investigated the associations between polymorphisms of CETP (mutations in intron 14 and exon 15, and Taq1B), hepatic lipase (C-514T), lipoprotein lipase ( PvuII and HindIII), and ATP-binding cassette transporter 1 (R219K) loci and longevity in 256 centenarians and 190 healthy younger controls. Although heterozygous CETP deficiency and the B2 allele of the Taq1B polymorphism was consistently associated with higher HDL-C concentrations both in centenarians and controls, the allelic frequencies of those polymorphisms did not differ between the two groups. The allelic frequencies of other gene polymorphisms in RCT were not different between the two groups. Centenarians with lipoprotein lipase P(-/-) genotype had significantly higher HDL-C concentration than those with P(-/+) or with P(+/+), in contrast, there was no such a relationship among controls. In stepwise multiple regression analysis, serum albumin, CETP deficiency and lipoprotein lipase PvuII genotype were independently associated with HDL-C in centenarians. Sex, CETP deficiency, and the Taq1B genotype were also independently associated with HDL-C; however, lipoprotein lipase PvuII genotype had no significant effect on their HDL-C in controls. In conclusion, we observed that CETP deficiency and other gene polymorphisms in RCT have no impact on longevity for Japanese centenarians.

Adult↗
PubMed2004

Fish protein improves blood pressure but alters HDL2 and HDL3 composition and tissue lipoprotein lipase activities in spontaneously hypertensive rats.

The two-month effects of dietary fish protein and casein on VLDL, HDL(2) and HDL(3) compositions and hepatic lipase (HTGL) and tissue lipoprotein lipase (LPL) activities were examined in spontaneously hypertensive rats (SHR) at 4 wk of age. After 2 mo of experiment, the fish protein diet induced lower blood pressure (-14 %) as compared to casein. Liver triacylglycerol and total cholesterol concentrations were 1.37- and 1.71-fold lower in the fish protein group than in the casein group, respectively. Total cholesterol concentration in plasma was also diminished by fish protein (-21 %) and was reflected in HDL(2) fraction (-44 %). SHR fed the fish protein diet as compared with those fed casein, showed a significantly low HDL(3) particle number, as measured by diminished HDL(3) mass and apo A-I. The consumption of fish protein did not affect VLDL particle number, but significantly decreased VLDL-triacylglycerol (-32 %) and adipose tissue total lipid concentrations as compared to casein. This was accompanied by diminished HTGL and adipose tissue LPL activities (-10%, -91%, respectively). These data demonstrate that fish protein plays an antihypertensive role and reduces plasma and tissue lipid concentrations. Thus, a fish protein intake might be beneficial for patients with hypertension.

Animals↗
PubMed2003

Lipoprotein lipase activator NO-1886.

Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride-rich lipoproteins such as very low-density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and a decrease in plasma high-density lipoprotein cholesterol (HDL-C). The increase in plasma TG and decrease in plasma HDL-C are risk factors for cardiovascular disease. Tsutsumi et al. hypothesized that elevating LPL activity would cause a reduction of plasma TG and an increase in plasma HDL-C, resulting in protection against the development of atherosclerosis. To test this hypothesis, Otsuka Pharmaceutical Factory, Inc. synthesized the LPL activator NO-1886. NO-1886 increased LPL mRNA and LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO-1886 also decreased plasma TG concentration and caused a concomitant rise in plasma HDL-C. Long-term administration of NO-1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortas. Multiple regression analysis suggested that the increase in plasma HDL-C and the decrease in plasma TG protect from atherosclerosis. The atherogenic lipid profile is changed to an antiatherogenic profile by increasing LPL activity, resulting in protection from atherosclerosis. Therefore, the LPL activator NO-1886 or other possible LPL activating agents are potentially beneficial for the treatment of hypertriglyceridemia, hypo-HDL cholesterolemia, and protection from atherosclerosis.

Animals↗
PubMed1998

Not the mature 56 kDa lipoprotein lipase protein but a 37 kDa protein co-purifying with the lipase mediates the binding of low density lipoproteins to J774 macrophages.

Lipoprotein lipase (LPL) purified from bovine milk showed variable abilities to stimulate the binding of low density lipoprotein (LDL) to J774 macrophages. The presence of a 37 kDa protein in the LPL sample seemed to be of importance for its stimulatory capacity. In order to investigate this, we isolated LPL from bovine milk via heparin Sepharose chromatography using a continuous salt gradient. Fractions containing the 37 kDa protein (as shown by SDS/PAGE under reducing conditions) eluted first from the column, followed by the 56 kDa LPL protein. The LPL enzymatic activity co-eluted with the 56 kDa protein, whereas the amount of 37 kDa protein fully paralleled the stimulatory effect on the binding of LDL to J774 cells. Samples not containing the 37 kDa protein were far less effective in stimulating the binding. Western blotting using a monoclonal antibody 5D2 against amino acids 396-405 in the carboxy-terminal domain of LPL, showed that the 37 kDa protein may be the C-terminal domain of LPL, presumably generated by proteolytic degradation of the mature LPL protein by milk proteases during its isolation. Furthermore, the functional mass of LPL for stimulation of the binding of LDL, as determined by radiation inactivation, was shown to be 30.9+/-1.8 kDa. We therefore suggest that cleavage of LPL at protease-sensitive sites causes a conformational change, generating an LPL protein which is more effective in mediating the binding and uptake of lipoproteins by cells.

Animals↗
PubMed1980

Breast milk jaundice; the role of lipoprotein lipase and the free fatty acids.

Lipoprotein lipase activity and free fatty acid concentrations were measured in samples of milk collected from mothers of infants without and with prolonged neonatal jaundice. The lipoprotein lipase and free fatty acid values in the milk from mothers of infants without jaundice were found to increase with the duration of breast-feeding until the 12th post-partum day, and then to fall to the original levels. In the group of mothers with jaundiced infants both lipoprotein lipase and free fatty acid values were found within normal limits when measured between 15th and 37th days post-partum. These findings indicate that increased values of lipoprotein lipase and free fatty acids in the milk are not responsible for the development of breast-milk jaundice.

Breast Feeding↗
PubMedDate not supplied

[Age characteristics of lipoprotein lipase activity and cholesterol levels in various lipoprotein fractions].

In practically healthy from 20 up to 95 years old persons, independently of sex, only slight alterations in the mean content of total cholesterol were noted. However, redistribution of cholesterol occurred between various classes of lipoproteins. There was a decrease of cholesterol content in high density lipoproteins (LPHD) and an increase in cholesterol content in lipoproteins of very low and low density. A positive correlation was found between the activity of postheparin lipoprotein lipase and the content of LPHD cholesterol, thus suggesting the essential role of the hydrolysis rate of triglycerides in the lipoproteins for regulation of LPHD cholesterol content, which are atherogenic factors in atherosclerosis development.

Adolescent↗
PubMed1986

CL-proteins and the regulation of lipoprotein lipase activity in locust flight muscle.

Lipoprotein lipases in the flight muscles of Locusta migratoria show a marked substrate specificity: diacylglycerols associated with the adipokinetic hormone (AKH)-induced lipoprotein, A+, are hydrolysed at 4 to 5 times the rate of those associated with the lipoprotein in resting (non-hormone-stimulated) locusts, Ayellow. To determine the basis for this discrimination, the effect on the activity of flight muscle lipoprotein lipase of CL-proteins, a major constituent of lipoprotein A+, but not of Ayellow, has been investigated; they inhibit the flight muscle enzyme in a competitive manner whether activity is measured with a natural lipoprotein substrate, a lipid emulsion or a water soluble substrate. Experiments in vivo suggest that the flight muscle enzyme is normally inhibited in resting (non-AKH-stimulated) locusts but, interestingly, injection of synthetic AKH-I relieves the inhibition and increases the activity by 30 to 40%. This is not a direct effect of the hormone on the enzyme, but appears to be related to the hormone-induced formation of lipoprotein A+, so that the majority of CL-proteins in the haemolymph become bound to this lipoprotein and the concentration of free CL-proteins is markedly reduced. We suggest that CL-proteins play a major role in the regulation of lipoprotein lipase in locust flight muscle.

Animals↗
PubMed1987

Brain lipoprotein lipase is responsive to nutritional and hormonal modulation.

Functional lipoprotein lipase activity was recently described in rat brain. The present study was performed to further characterize the biologic significance of brain lipoprotein lipase (heparin releasable component) and elucidate regulatory factors. Comparative studies were performed on tissue (brain, adipose, and heart) heparin releasable lipoprotein lipase in the fasted and diabetic (streptozotocin 100 mg/kg BW IP) rat. Both fasting (96 hours) and diabetes (ten days) significantly decreased brain (cortical) (P less than .05) and adipose (epididymal fat pad) (P less than .001) lipoprotein lipase activity. In contrast, heart muscle enzyme activity was significantly increased (P less than .001) in response to fasting and diabetes. Refeeding (Purina chow 96 hours) and insulin replacement (96 hours) reversed these changes in tissue lipoprotein lipase consequent to fasting and diabetes, respectively. There was a positive correlation between the changes in serum insulin concentration and adipose lipoprotein lipase, but there was no correlation between this parameter and brain or heart lipoprotein lipase. In addition, although T3 therapy normalized the low T3 state associated with both fasting and diabetes, it had no effect on the enzyme activity in the studied tissues. However, subsequent studies demonstrated that hypothyroidism (2 weeks post thyroidectomy) significantly decreased brain lipoprotein lipase activity (P less than .001) and increased both the adipose (P less than .025) and heart (P less than .025) enzyme activity. T3 replacement (0.8 micrograms/100 BW/d for 1 week) reversed the effects of hypothyroidism. However, the relationship between brain enzyme activity and serum T3 was nonlinear as hyperthyroidism tended to reduce brain LPL activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗