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PubMed1988

Is vitellogenin an ancestor of apolipoprotein B-100 of human low-density lipoprotein and human lipoprotein lipase?

Vitellogenin, an ancient animal protein, is the major yolk protein of eggs, where it is used as a food source during embryogenesis. Here it is shown that vitellogenins, including those from the invertebrates Caenorhabditis elegans and Drosophila melanogaster, contain domains that are homologous with parts of apolipoprotein B-100 (apoB-100) of human low-density lipoprotein and human lipoprotein lipase. As vitellogenins are likely to have been used by invertebrates during embryogenesis well before the circulation of lipids appeared in vertebrates, it is suggested that copies of a precursor gene, serving a function similar to vitellogenin, were modified to code for part of apoB-100 and lipoprotein lipase in vertebrates. In addition to providing a link between invertebrates and vertebrates for proteins involved in lipid transport, these homologies suggest new functions for vitellogenin other than being a yolk food for the developing embryo.

Amino Acid Sequence↗
PubMed2002

Lipoprotein lipase deficiency and CETP in streptozotocin-treated apoB-expressing mice.

Both hyperglycemia and hyperlipidemia have been postulated to increase atherosclerosis in patients with diabetes mellitus. To study the effects of diabetes on lipoprotein profiles and atherosclerosis in a rodent model, we crossed mice that express human apolipoprotein B (HuB), mice that have a heterozygous deletion of lipoprotein lipase (LPL1), and transgenic mice expressing human cholesteryl ester transfer protein (CETP). Lipoprotein profiles due to each genetic modification were assessed while mice were consuming a Western type diet. Fast-protein liquid chromatography analysis of plasma samples showed that HuB/LPL1 mice had increased VLDL triglyceride, and HuB/LPL1/CETP mice had decreased HDL and increased VLDL and IDL/LDL. All strains of mice were made diabetic using streptozotocin (STZ); diabetes did not alter lipid profiles or atherosclerosis in HuB or HuB/LPL1/CETP mice. In contrast, STZ-treated HuB/LPL1 mice were more diabetic, severely hyperlipidemic due to increased cholesterol and triglyceride in VLDL and IDL/LDL, and had more atherosclerosis.

Animals↗
PubMed1995

DNA polymorphisms at the lipoprotein lipase gene are associated with macroangiopathy in type 2 (non-insulin-dependent) diabetes mellitus.

We studied the effect of variation at the lipoprotein lipase (LPL) gene locus on the susceptibility of individuals with Type 2 diabetes mellitus to atherosclerotic vascular disease in a population of 126 male and 114 female patients. The prevalence of any evidence of coronary heart disease (CHD) (presence of ischaemic ECG changes or definite myocardial infarction) was low in the patients who were homozygous for the presence of the PvuII restriction site (genotype 2-2) (40.9%) compared with those who were heterozygous (genotype 1-2) (57.9%; P = 0.05) or homozygous for the absence of it (genotype 1-1) (61.9%; P < 0.04). In men, a clear gene dosage effect on CHD was seen, the genotype 2-2 patients having the lowest (39.1%), the 1-2 patients an intermediate (49.3%) and the 1-1 patients the highest (61.1%) frequency of coronary disease. Patients with the genotype 2-2 of the HindIII polymorphism (absence of the restriction site) had the highest prevalence of any evidence of CHD (90.0%) compared with the genotype 1-2 (heterozygotes for the presence of the restriction site) (55.4%) or 1-1 (presence of the restriction site) (54.6%; P < 0.03). Stepwise discriminant analysis revealed that in the whole diabetic population the PvuII genotype of the LPL gene was independently and significantly associated with CHD but its effect decreased when the plasma lipids were taken into account. Overall, this study demonstrates the role of the PvuII polymorphism in the LPL gene to modulate the risk for diabetic macroangiopathy in patients with Type 2 diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1995

[Alcohol-induced hypertriglyceridemia in subjects with decreased lipoprotein lipase--improvement after cessation of alcohol intake].

We systematically investigated the effect of lipoprotein lipase (LPL) and alcohol intake on the development of primary type IV hyperlipoproteinemia which is manifested as a moderate increase in serum triglycerides as a consequence of an elevated very low density lipoprotein concentration and a normal level of serum cholesterol. Twenty six type IV hyperlipoproteinemic and 28 normolipidemic males underwent measurement of the immunoreactive LPL mass in postheparin plasma (30 unit of heparin/kg of body weight) and were interviewed as to their alcohol consumption. They were divided into 4 groups, with a LPL mass of 150ng/ml (20 percentile of the normal range) and an alcohol intake of 33g/day as the borderlines. All subjects with LPL mass less than 150ng/ml and alcohol intake of more than 33g/day were prone to manifest type IV hyperlipoproteinemia. One of the subjects in this group showed a recovery to normolipidemic state after cessation of alcohol intake. Subject whose LPL mass value was more than 180ng/ml (50 percentile of the normal range) were not susceptible to type IV hyperlipoproteinemia even though they drank alcohol more than 33g/day.

Alcohol Drinking↗
PubMed1990

Interaction of lipoprotein lipase with glycosaminoglycans and apolipoprotein C-II: effects of free-fatty-acids.

Lipoprotein lipase (LPL) bound to endothelial cells is released from the cell surface by triacylglycerol-rich lipoproteins and oleic acid (Saxena, U., Witte, L.D. and Goldberg, I.J. (1989) J. Biol. Chem. 264, 4349-4355). Studies were conducted to compare the ability of different fatty acids to release 125I-labelled bovine milk LPL bound to endothelial cells and to define the mechanism for this effect. Using fatty acid/bovine serum albumin (BSA) solutions (molar ratio, 6:1), the release of LPL from endothelial cell surfaces using monounsaturated (18:1), polyunsaturated (18:2) and saturated (16:0) fatty acids was 78%, 60% and 28%, respectively. Release of LPL from heparin-agarose followed a similar pattern, suggesting that the fatty acids specifically affected LPL-heparin interaction. Short-chain fatty acids (C6, C8 and C10), medium-chain fatty acids (C12 and C14) and elaidic acid, a transisomer of oleic acid, released less 125I-LPL than oleic acid from heparin-agarose. To determine whether oleic acid release of 125I-LPL from heparin-agarose was due to binding of the fatty acid to heparin or LPL, oleic acid was incubated with either LPL or heparin-agarose prior to performing the affinity chromatography. Only the prior incubation with LPL affected the binding to heparin-agarose. This demonstrates that dissociation of LPL from heparin required interaction of fatty acid with LPL. At high molar ratios of fatty acid:BSA (greater than 3:1), apo C-II is known to be ineffective as an activator of LPL. To determine whether this effect is due to decreased association of apo C-II with LPL, 125I-apo C-II (0.5-10 nmol) was allowed to bind to LPL-Sepharose. A 6:1 molar ratio of oleic acid:BSA produced up to 69% decrease in the amount of 125I-apo C-II bound to the gel. This dissociation of apo C-II from LPL by oleic acid was also demonstrated using gel-filtration chromatography. Thus, the amount and type of fatty acids may be important in regulating LPL activity in vivo by affecting both LPL interaction with glycosaminoglycans and with apo C-II.

Animals↗
PubMed1995

The mutant Asn291-->Ser human lipoprotein lipase is associated with reduced catalytic activity and does not influence binding to heparin.

Lipoprotein lipase (LPL) plays a central role in triglyceride metabolism, regulating the catabolism of triglyceride-rich lipoprotein particles. LPL performs its hydrolytic action attached to heparan sulfate proteoglycans at the luminal surface of capillary endothelial cells. We have assessed the effect of the Asn291-->Ser (N291S) substitution found in LPL gene from a human hyperlipemic patient. Our results showed that both the wild-type (WT) and N291S hLPL expressed in COS1 cells were secreted to the extracellular medium, and presented similar intracellular distribution patterns. Furthermore, heparin-Sepharose affinity chromatography assays revealed normal heparin affinity of the N291S hLPL. In addition, both the mutant and the WT protein bound to the surface of human fibroblasts and untransfected COS1 cells. Interestingly, diminished LPL specific activity was observed in the extracellular medium from mutant expressing cells. Therefore the lack of normal LPL activity in patients harbouring such a mutation could be the cause of their hyperlipemic disorder.

Base Sequence↗
PubMed2000

Frequency and allelic association of common variants in the lipoprotein lipase gene in different ethnic groups: the Wandsworth Heart and Stroke Study.

The lower serum triglyceride (Tg), higher high density cholesterol (HDL-C) levels and low coronary heart disease (CHD) mortality in black populations, contrast with that in whites. By comparison, South Asian populations display a higher mortality from CHD associated with increased Tg and low HDL-C levels. Lipoprotein lipase (LPL) plays a major role in Tg metabolism. To determine if variation in the LPL gene contributes to the differences in lipid levels, we studied the frequencies and allelic associations of five common variants in the lipoprotein lipase (LPL) gene (-93T/G, D9N, N291S, S447X, and the HinddIII RFLP in intron 8) with serum Tg and HDL-cholesterol concentrations in population samples of middle-aged men and women of whites, South Asians, and blacks of African origin co-resident in South London. Significantly higher frequencies of the H(-) (P < 0.00001), N9 (P < 0.001), and -93G (P < 10(-10)) alleles were seen in blacks compared to the other two groups. Allelic association between -93G and N9, and H(+) and X447 was strong in all three groups. However, no association was observed between serum Tg and HDL-cholesterol concentrations and these variants in the three ethnic groups. A single common polymorphism in the LPL gene is unlikely to account for the differences in fasting serum Tg in populations of different ethnic background. The importance of the differences in frequencies and the mechanism(s) whereby these may contribute towards a beneficial LPL genotype in black populations remain to be determined.

Adult↗
PubMed2000

Very-low-density lipoprotein binding to the apolipoprotein E receptor 2 is enhanced by lipoprotein lipase, and does not require apolipoprotein E.

The apolipoprotein (apo)E receptor 2 (apoER2) is a recently cloned member of the low-density lipoprotein (LDL) receptor (LDLR) family, showing a high homology with both the LDLR and the very-low-density lipoprotein (VLDL) receptor (VLDLR). In the present study, the binding characteristics of the apoER2 with respect to apoE and lipoprotein lipase (LPL) were investigated. VLDL was isolated from both apoE-deficient mice and mice expressing the human APOE2 (Arg(158)-->Cys) and APOE3-Leiden isoforms on an Apoe(-/-),Ldlr(-/-) double knock-out background. apoE-rich rabbit beta-VLDL was used as a positive control for binding. Binding experiments performed with Chinese hamster ovary cells expressing the human apoER2 showed that the receptor was able to bind VLDL containing either of the apoE isoforms, as well as the apoE-deficient VLDL. Hence, in contrast with the VLDLR, the apoER2 is not strictly dependent on apoE for VLDL binding. Since LPL has been shown to enhance the binding of lipoproteins to several members of the LDLR family, including the LDLR-related protein, VLDL receptor, gp330 and the LDLR itself, VLDL binding experiments were performed in the presence of LPL. Addition of LPL resulted in a significant increase in apoER2 binding for all VLDL fractions used in this study. In conclusion, lipoprotein binding of VLDL to the apoER2 is enhanced in the presence of LPL, and is not restricted to apoE-containing lipoproteins.

Animals↗
PubMed1977

Purification of bovine milk lipoprotein lipase with the aid of detergent.

The present study describes a simple method for the purification of bovine milk lipoprotein lipase based on affinity chromatography on agarose containing covalently linked heparin and the use of a non-ionic detergent, Triton X-100. By this procedure miligram amounts of detergent-free lipoprotein-ionic lipase with a specific activity of 28.9 mmoles free fatty acid/mg protein/mg protein/hour can be obtained. The apparent molecular weight of the polypeptide as determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate is 55,000. The purified triacylglycerol lipase also hydrolyzes monoacylglycerol, but the activity against this lipid is 40 times lower than that against triacylglycerol.

Animals↗
PubMed1986

Effects of dextran sulfate on stabilization of milk lipoprotein lipase and VLDL triglyceride hydrolysis in vitro.

The effects of dextran sulfate (DS), which has various molecular numbers, on hydrolysis of very low density lipoprotein triglyceride (VLDL-TG) by bovine milk lipoprotein lipase (LPL) and the stability of LPL were studied. VLDL-TG hydrolysis was increased by the addition of DS; DS caused linear increase in the Vmax for VLDL-TG with increase in its sulfate content, but did not change the Km value for VLDL-TG. DS also stabilized LPL, but this effect was not dependent on its sulfate content. These results suggest that the mechanism of action of DS in LPL stabilization may be different from that in enhancement of VLDL hydrolysis.

Animals↗
PubMed1978

Lipoprotein-lipase activity in human skeletal muscle and adipose tissue in the fasting and the fed states.

Sixteen healthy subjects, 7 females and 9 males, with a mean age of 25 years (range 22--29 years), were studied in the fasting state in the morning and 8 h later after partaking of breakfast, lunch and two small meals. The lipoprotein-lipase activity in the adipose tissue increased significantly from 80 +/- 32 to 117 +/- 61 nmol fatty acid released per gram and minute (nmol FA/g/min), whereas in skeletal-muscle tissue it decreased significantly from 25 +/- 11 to 17 +/- 9 nmol FA/g/min. The concentration of serum triglycerides increased significantly from 0.93 +/- 0.18 mmol/l (mean +/- SD) in the fasting state to 1.57 +/- 0.64 mmol/l in the fed state. In the fasting state the lipoprotein-lipase activity of skeletal muscle was inversely related to the ratio between the concentrations of insulin and glucagon.

Adipose Tissue↗
PubMed1985

Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III.

From a total of 22 hypertriglyceridemic subjects tested, 14 subjects were selected on the basis of normal postheparin plasma lipoprotein lipase (LPL) levels and the presence of LPL inhibitory activity in their fasting plasma. The inhibitory activity was detected in both the lipoprotein fraction (d less than 1.25 g/ml) and the lipoprotein-deficient fraction (d greater than 1.25 g/ml). Correlational analyses of LPL inhibitory activity and apolipoprotein levels present in the lipoprotein fraction (d less than 1.25 g/ml) indicated that only apolipoprotein C-III (ApoC-III) was significantly correlated (r = 0.602, P less than 0.05) with the inhibition activity of the lipoprotein fraction. Furthermore, it was found that LPL-inhibitory activities of the plasma lipoprotein fraction and lipoprotein-deficient fraction were also correlated (r = 0.745, P less than 0.005), though the activity in the lipoprotein-deficient plasma was not related to the ApoC-III or apolipoprotein E levels. Additional correlational analyses indicated that the LPL levels in the postheparin plasma of these subjects were inversely related to the levels of plasma apolipoproteins C-II, C-III, and E. To explain some of these observations, we directly examined the in vitro effect of ApoC-III on LPL activity. The addition of ApoC-III-2 resulted in a decreased rate of lipolysis of human very low density lipoproteins by LPL. Kinetic analyses indicated that ApoC-III-2 was a noncompetitive inhibitor of LPL suggesting a direct interaction of the inhibitor with LPL. Results of these studies suggest that ApoC-III may represent a physiologic modulator of LPL activity levels and that the incidence of LPL inhibitory activity in the plasma of hypertriglyceridemic subjects is more common than previously recognized.

Adult↗
PubMed2004

Triacylglycerol-rich lipoprotein margination: a potential surrogate for whole-body lipoprotein lipase activity and effects of eicosapentaenoic and docosahexaenoic acids.

BACKGROUND: Margination occurs when blood borne particles attach to the vessel wall. Triacylglycerol-rich lipoprotein (TRL) particles marginate when they bind to endothelial lipoprotein lipase (LpL). OBJECTIVE: This study was undertaken to determine whether TRL margination reflects in vivo LpL activity and whether n-3 fatty acids affect fasting and fed TRL margination. DESIGN: Healthy subjects (n = 33) began with a 4-wk, placebo (olive oil; 4 g/d) run-in period and were then randomly assigned to 4 wk of treatment with 4 g/d of ethyl esters of either safflower oil (SAF; control), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA). Margination volume (MV) was calculated by subtracting true from apparent plasma volume. RESULTS: MVs were 3 times as great during the fasting state as during the fed state (P < 0.0001). In both the fasting and the fed states, MV was significantly correlated with plasma triacylglycerol and TRL half-lives. In the fed state, MV was also correlated with preheparin LpL, whereas in the fasting state it was not. There was no significant correlation between preheparin LpL and postheparin LpL in the fasting state. Relative to SAF, EPA and DHA supplementation resulted in higher MVs by 64% and 53% (both P < 0.001), respectively, in the fasting state, without significantly reducing fasting triacylglycerol concentrations. In the fed state, DHA doubled the MV (P < 0.05), whereas EPA had no significant effect. CONCLUSIONS: The correlations between MV and TRL half-lives and preheparin LpL suggest that MV could be a reflection of whole-body LpL binding capacity. The increases in MVs with EPA and DHA supplementation suggest that these fatty acids may increase the amount of endothelial-bound LpL or its affinity for TRL.

Administration, Oral↗
PubMed2006

Impact of native VLDL on tissue factor pathway inhibitor in endothelial cells and interactions between TFPI and lipoprotein lipase.

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of tissue factor (TF)-induced blood coagulation. A positive association between very low density lipoproteins (VLDLs) and TFPI has been reported in vivo. In contrast, one in vitro study indicates that TFPI may enhance lipoprotein lipase (LPL) activity, thereby increasing triglyceride hydrolysis. The current study was conducted to investigate how native VLDL influenced the synthesis and release of TFPI in endothelial cells, and how TFPI affected the LPL-induced hydrolysis of VLDL in vitro and at the endothelial surface. A spontaneously transformed immortal endothelial cell line (ECV304) and primary coronary artery cells (CoEc) were used, and VLDL was isolated from healthy volunteers by density gradient ultracentrifugation. Sequential free fatty acid (FFA) measurements were used to evaluate the kinetics of the LPL-induced hydrolysis. The levels of TFPI mRNAs in the stimulated cells were determined by quantitative real-time reverse transcription-ploymerase chain reaction (qPCR) using the ABI PRISM 7700 Sequence Detection System. Stimulation of ECV304 cells for 24 hours with native VLDL (0-100 microg/mL) caused a dose-dependent increase of TFPI in the medium (6.7-23.8 ng/10(6) cells, P < 0.001), without affecting the cellular content of TFPI. The expression of TFPI mRNA was significantly upregulated after 10 minutes of stimulation with n-VLDL. Both recombinant TFPI (r-TFPI) and LPL showed a dose-dependent binding to ECV 304 cells without saturation, and no competitive binding interactions between LPL and TFPI were observed at the endothelial surface. The addition of increasing concentrations of r-TFPI to ECV 304 cells, preincubated with LPL, did not affect the hydrolysis of VLDL triglycerides. The maximal reaction velocity (V(max)) of LPL-induced hydrolysis of n-VLDL was not affected by the addition of increasing concentrations of r-TFPI to the reaction mixture in vitro. The current experimental study indicates an upregulation of TFPI synthesis and release by VLDL. LPL-induced hydrolysis of VLDL in vitro was not influenced by TFPI neither in suspension nor at the endothelial surface.

Cell Line↗
PubMed2006

Preclinical investigations of a medium-chain triglyceride:fish oil emulsion. I. Effects of bovine milk lipoprotein lipase on lipid composition.

The bolus intravenous injection of a novel medium-chain triglyceride:fish oil emulsion (MCT:FO, 8:2, w:w) was recently found to increase within 60 min the leucocyte and platelet phospholipid content of long-chain polyunsaturated omega3 fatty acids. The present report deals with the effects of bovine milk lipoprotein lipase on the lipid composition of this emulsion. The results are compared to those obtained with either a pure fish oil emulsion or a medium-chain triglyceride: long-chain triglyceride:fish oil emulsion (MLF, 5:4:1). Emphasis is placed on i) differences in the fate of distinct fatty acids initially present in the triglycerides, di glycerides and phospholipids, ii) the generation of unesterified fatty acids relative to their initial content in each emulsion, and iii) the time course for these various events. The comparison between the three emulsions under consideration also provides information relevant to their respective sensitivity to lipoprotein lipase and suitability in terms of the generation of distinct unesterified fatty acids, including long-chain polyunsaturated omega3 fatty acids. Furthermore, attention is drawn to the greater efficiency for the hydrolysis of fatty acids from diglycerides as compared to triglycerides and a transient increase in the paired C8:0/C10:0 ratio in the diglycerides generated from the MCT:FO or MLF emulsion. The present study thus affords novel information relevant to the possible use of the MCT:FO emulsion in human subjects.

Animals↗
PubMed1985

Diurnal course of the suitability of serum samples obtained from normal subjects and from patients with primary endogenous hypertriglyceridaemia to serve as substrate for milk lipoprotein lipase.

Serum samples, obtained at various times of the day from four normal subjects and five patients with primary endogenous hypertriglyceridaemia on a carbohydrate-rich diet (meals at 09.00, 13.00 and 17.00 h), were incubated with cows' milk lipoprotein lipase (LPL) to investigate the susceptibility of the triglyceride(TG)-rich lipoprotein fraction to hydrolysis. Mean KM and vmax of this reaction increased in patients between 09.00 and 13.00 h (p = 0.016 and 0.015, respectively) and decreased again thereafter, whereas no diurnal change was observed in normal subjects (p = 0.31 and 0.27, respectively). At 13.00 and 23.00 h patients showed a higher mean KM (p less than 0.02) at 23.00 h a higher mean vmax (p less than 0.03) than normal subjects. When the data were expressed as reaction rates (FFA formation rates) at TG-concentrations in the in vivo range, neither group showed a diurnal difference. Patients showed a significantly lower reaction rate than normal subjects only at 13.00 h at TG concentrations below 3 mmol X 1-1. This suggests that a defect in the suitability of TG-rich particles to serve as a substrate for LPL is not likely to play a role in the development of hypertriglyceridaemia.

Adult↗
PubMed1992

Refeeding meal-fed rats increases lipoprotein lipase activity and deposition of dietary [14C]lipid in white adipose tissue and decreases oxidation to 14CO2. The role of undernutrition.

Meal-fed (3 h) rats had a decreased food intake, body weight and carcass fat compared with rats fed ad libitum. On refeeding a chow meal containing [1-14C]triolein, the production of 14CO2 was lower (45%) and the accumulation of carcass [14C]lipid higher (37%) in the meal-fed rats. There was higher lipoprotein lipase activity and greater accumulation of [14C]lipid in the epididymal and subcutaneous adipose-tissue depots of the meal-fed rats. In contrast, heparin-releasable lipoprotein lipase was not increased in perfused hearts of meal-fed rats on refeeding. Return of meal-fed rats to feeding ad libitum reversed these changes before the restoration of body weight or carcass fat. Evidence is presented that decreased dietary intake rather than meal pattern is an important determinant of the alterations in adipose lipid metabolism in the meal-fed rat in response to a meal.

Adipose Tissue↗