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PubMed1993

Two DNA polymorphisms in the lipoprotein lipase gene and their associations with factors related to cardiovascular disease.

Lipoprotein lipase (LPL) plays a crucial role in plasma lipoprotein processing by catalyzing the hydrolysis of core triglycerides of chylomicrons and very low density lipoproteins. Several polymorphic restriction sites have been reported in the LPL gene, including those identified by the enzymes HindIII and PvuII. We have determined the HindIII and PvuII polymorphisms in diabetic (D) and non-diabetic (ND) Hispanics (D = 195; ND = 384) and non-Hispanic Whites (D = 76; ND = 539) from the San Luis Valley, Colorado. Both polymorphisms showed comparable gene frequencies between diabetics and non-diabetics, and between the two ethnic groups. The HindIII and PvuII polymorphisms were in strong linkage disequilibrium in both Hispanics and non-Hispanic Whites (P < 0.001). We estimated whether the two DNA polymorphisms have significant impact in determining interindividual differences in plasma levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, fasting glucose, and fasting insulin. Plasma triglyceride levels varied significantly among the HindIII genotypes in the normoglycemic sample. There was a clear gene dosage effect among the three HindIII genotypes, with the (-/-) genotype having the lowest and the (+/+) genotype having the highest triglyceride levels; these levels were intermediate in the (+/-) genotype. The average effect of the (-) allele of the HindIII polymorphism was to lower triglycerides by 12.85 mg/dl in non-Hispanic White males, 8.06 mg/dl in non-Hispanic White females, 10.91 mg/dl in Hispanic males, and 12.47 mg/dl in Hispanic females. The HindIII polymorphism also showed a significant association with HDL-cholesterol levels in the normoglycemic sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2002

Activity and concentration of lipoprotein lipase in post-heparin plasma and the extent of coronary artery disease.

Numerous studies have found polymorphisms in the lipoprotein lipase (LPL) gene to be associated with the risk of coronary artery disease (CAD), implicating LPL in the development of atherothrombotic disease. It remains controversial, however, whether LPL acts in a pro- or anti-atherogenic fashion. We quantitated activity and concentration of LPL in post-heparin plasma from 194 male patients undergoing coronary angiography. HDL cholesterol was significantly associated with LPL activity quartiles (1.09+/-0.26 the highest vs. 0.96+/-0.25 mmol/l the lowest quartile, P<0.01). There was also a trend towards higher total (5.61+/-1.33 vs. 5.16+/-1.44 mmol/l, P=0.059) and LDL cholesterol (3.92+/-1.39 vs. 3.46+/-1.06 mmol/l, P=0.09) with higher LPL activity. In contrast, measures of CAD extent showed no differences between LPL quartiles (P>0.30 for prior myocardial infarction, number of diseased vessels, Gensini and extent scores). Additionally, there was no difference in LPL activity (CAD: n=158, 168+/-70 nmol/ml/min, no CAD: n=36, 180+/-89 nmol/ml/min, P=0.47) or concentration (280+/-121 ng/ml and 288+/-111 ng/ml, P=0.72) between patients with and without CAD. Our data show that, in spite of an association with lipoprotein parameters, LPL in post-heparin plasma is unrelated to the presence or the extent of CAD. Therefore, lipoprotein lipase determination in plasma does not appear to be a useful marker in the assessment of CAD risk.

Aged↗
PubMed1971

A method for the determination of lipoprotein lipase in postheparin plasma and body tissues utilizing a triolein-coated Celite substrate.

A simple and specific method for assaying lipoprotein lipase activity is described. Postheparin plasma, heart homogenates, or extracts of acetone powder of adipose tissue were incubated with a triolein-coated Celite substrate, and enzyme activity was determined from the rate of free fatty acid (FFA) release in the incubation system. FFA release was linear for 30 min, and was proportional to protein concentration in the incubation system. FFA release was decreased by addition of deoxycholate or Triton X-100. Increasing the concentration of heparin in the incubation system caused a gradual decrease in FFA release by postheparin plasma and increases in activity of heart homogenates and adipose tissue lipoprotein lipase. The Celite substrate was found to be satisfactory for assaying pancreatic lipase activity as well.

Adipose Tissue↗
PubMed1997

The novel compound NO-1886 elevates plasma high-density lipoprotein cholesterol levels in hamsters and rabbits by increasing lipoprotein lipase without any effect on cholesteryl ester transfer protein activity.

Lipoprotein lipase (LPL) and cholesteryl ester transfer protein (CETP) are determinants of high-density lipoprotein (HDL) cholesterol concentrations in plasma. We have previously reported that NO-1886, by increasing LPL activity, causes elevation of HDL cholesterol levels in rats. In the present study, we studied the effect of NO-1886 on CETP activity in experimental animals. Since previous reports suggest that rats may lack CETP, we examined hamsters and rabbits, as well as rats. We found that NO-1886 increased LPL activity, resulting in elevation of plasma HDL cholesterol in all three animals. We confirmed that rats lack CETP and that both hamsters and rabbits have high CETP activity. NO-1886 had no effect on CETP activity in hamsters and rabbits. These results demonstrate that the compound NO-1886 elevates HDL cholesterol in experimental animals by selectively increasing LPL activity without any effect on CETP. Animals with low CETP and high LPL activities appear to be more sensitive to NO-1886 than those with high CETP and low LPL activities.

Animals↗
PubMed2006

Lipoprotein lipase S447X: a naturally occurring gain-of-function mutation.

Lipoprotein lipase (LPL) hydrolyzes triglycerides in the circulation and promotes the hepatic uptake of remnant lipoproteins. Since the gene was cloned in 1989, more than 100 LPL gene mutations have been identified, the majority of which cause loss of enzymatic function. In contrast to this, the naturally occurring LPL(S447X) variant is associated with increased lipolytic function and an anti-atherogenic lipid profile and can therefore be regarded as a gain-of-function mutation. This notion combined with the facts that 20% of the general population carries this prematurely truncated LPL and that it may protect against cardiovascular disease has led to extensive clinical and basic research into this frequent LPL mutant. It is only until recently that we begin to understand the molecular mechanisms that underlie the beneficial effects associated with LPL(S447X). This review summarizes the current literature on this interesting LPL variant.

Animals↗
PubMed1989

Effect of tumor necrosis factor administration in vivo on lipoprotein lipase activity in various tissues of the rat.

When added to murine adipocytes in culture, tumor necrosis factor (TNF) decreases the levels of lipoprotein lipase (LPL). Semb et al (1987. J. Biol Chem. 262: 8390-8394) have shown that administration of murine TNF to rats decreases lipoprotein lipase (LPL) in the epididymal fat pad with maximal inhibition requiring several hours. We have now tested the effects of treatment of rats with TNF on LPL activity in a variety of tissues and find that few show decreases in LPL under conditions that acutely increase serum triglycerides. Ninety minutes after treatment of male rats with human TNF (25 micrograms/200 g, i.v.), serum triglycerides rose 2.2-fold but there was no decrease in LPL activity in epididymal fat. Sixteen hours after TNF treatment LPL activity had decreased by 44% in epididymal fat, consistent with the previously reported data. In contrast, in female rats, no significant decrease was seen in LPL activity in parametrial adipose tissue at either 90 min or 16 hr after TNF administration despite increases in serum triglycerides (1.8-fold and 1.5-fold, respectively). There was little change in LPL activity in most other adipose tissue sites of male or female rats at either time after TNF treatment. No effect of TNF was seen on heart or diaphragm muscle LPL at any time. TNF treatment of both male and female rats produces consistent increases in de novo hepatic lipogenesis in vivo under conditions that increase serum triglycerides. It is unlikely that the limited effects of TNF on LPL in vivo can account for the rapid and sustained increase in serum triglycerides.

Adipose Tissue↗
PubMed1997

Gene expression of lipoprotein lipase in experimental nephrosis.

Nephrotic syndrome (NS) is commonly associated with marked hypertriglyceridemia, impaired triglyceride-laden lipoprotein clearance, and reduced peripheral tissue uptake of triglycerides from chylomicrons. Lipoprotein lipase (LPL) is the rate-limiting step in triglyceride-rich lipoprotein metabolism. Earlier studies have demonstrated a marked reduction of plasma post-heparin lipolytic activity and LPL protein in NS. However, the effect of NS on gene expression of LPL has not been elucidated. We studied rats with puromycin aminonucleoside-induced NS and the placebo-injected control animals. Heart, soleus muscle, and fat body LPL activity, protein mass, and mRNA were measured and plasma lipid levels were quantitated. The NS group exhibited marked proteinuria, hypoalbuminemia, and hypertriglyceridemia. This was associated with significant reductions of LPL activity and immunodetectable protein in the heart, adipose tissue, and soleus muscle in the NS group. The reduction in LPL protein mass in the tissues tested was accompanied by a parallel reduction in LPL mRNA of the heart but not of either adipose tissue or skeletal muscle, suggesting translational or posttranslational modifications. A negative correlation was found between plasma triglyceride concentration and the LPL, activities of the tissues tested in the study population. Thus this study has revealed a significant down-regulation of tissue LPL protein in experimental NS. This phenomenon can, in part, account for hypertriglyceridemia, impaired catabolism of chylomicrons, and very low-density lipoprotein by peripheral tissues and decreased postheparin lipolytic activity in NS.

Adipose Tissue↗
PubMed2000

Lipoprotein lipase gene polymorphism, cholesterol subfractions and myocardial infarction in large samples of the general population.

OBJECTIVE: Genetic variants of the lipoprotein lipase gene have been associated with dyslipidemia and coronary artery disease. However, data have been inconsistent and are mainly based on selected predominantly male patient groups. METHODS: We evaluated the influence of the HindIII restriction fragment length polymorphism on lipid levels in the general population (1361 participants of a large population-based survey from Augsburg, Germany; 50% women) as well as the association of this polymorphism with the risk of myocardial infarction (MI; genotype frequencies in 1159 patients with documented MI under 60 years of age). RESULTS: In the population-based survey, a highly significant association between the frequent H2H2 genotype and unfavorable cholesterol subfraction levels was observed in men and in postmenopausal women whereas no significant association was observed in premenopausal women (uni- and multivariate analysis). Such unfavorable lipid levels in homozygotes for the H2 allele may be expected to be associated with a 19-25% increased risk to suffer from myocardial infarction (MI). Nevertheless, genotype and allele frequencies in the general population were not different from those in patients with previous MI (H2H2 genotype frequency 51.3% vs. 53.2%, respectively; P=0.63). CONCLUSION: This large study shows that the H2H2 genotype of the lipoprotein lipase gene polymorphism is associated with unfavorable lipid levels. Estrogen status may modulate this association in women. The effects of the genotype on lipid levels were apparently not strong enough to reveal a significant association with MI.

Adult↗
PubMed1984

Modified lipoprotein lipase catalyzes ester synthesis in benzene. Substrate specificity.

Modified lipoprotein lipase catalyzed the synthesis of trilaurin from mono- or diacylglycerol and fatty acid and also the synthesis of ester from fatty acid and alcohol in benzene. In the ester synthesis reaction, the longer the chain length of fatty acid or alcohol, the higher the ester synthesis activity. The ester synthesis was competitively inhibited by fatty acids with branch of carbon chain at the position neighboring the carboxyl group. Other substrates including secondary and tertiary alcohols and carboxylic acids having benzene ring were tested and discussed in relation to the ester synthesis.

Benzene↗
PubMed1994

Interactions of lipoprotein lipase with the active-site inhibitor tetrahydrolipstatin (Orlistat).

Lipoprotein lipase (LPL) was rapidly inactivated by low concentrations of the active-site inhibitor tetrahydrolipstatin (THL). The presence of amphiphils (e.g. long-chain fatty acids) or of lipid/water interfaces (lipid emulsions) was required for inhibition to occur. Apolipoprotein CII increased the maximal inactivation rate constant by 1.8-fold in the presence of an emulsion of long-chain triacylglycerols, but had no effect in the presence of an emulsion of tributyrylglycerol. The fully inhibited enzyme had a ratio of THL/LPL of nearly 2, indicating that both subunits of the LPL homo-dimer bound THL. The THL-LPL complex was stable below pH 7.5. At higher pH reactivation occurred indicating that THL was slowly turned over by the enzyme. The apparent reactivation rate constant was increased about threefold by the presence of lipid/water interfaces. Sucrose density gradient centrifugation revealed that THL induces tetramerisation of LPL. This aggregation was reversible on reactivation of the inhibited enzyme. Binding to heparin was not affected by THL. In contrast, binding to lipid droplets and to lipoproteins was increased, indicating exposure of hydrophobic regions in the inhibited LPL. It is suggested that THL induces local conformational changes in LPL, which may involve opening of the putative surface lid structure which covers the active-site.

Animals↗
PubMed1992

Mapping of the epitope on lipoprotein lipase recognized by a monoclonal antibody (5D2) which inhibits lipase activity.

A monoclonal antibody, 5D2, which inhibits human lipoprotein lipase (hLPL) activity has been widely used for assessment of LPL immunoreactive mass in the clinical evaluation of patients [1] and for analysis of structure-function relationships of LPL [2,3]. We have mapped the epitope on LPL, recognized by the 5D2 antibody, within residues 396-405. Ala400 is the critical amino acid residue conferring epitope specificity. This knowledge confirms that the C-terminal domain of LPL plays a critical role in LPL activity and also provides important information for studies exploring the structure-function relationship of LPL using this antibody.

Amino Acid Sequence↗
PubMed1979

Developmental pattern of pulmonary lipoprotein lipase in growing rats.

The developmental pattern of pulmonary lipoprotein lipase (LPL) activity was measured in growing male and female rats from the neonatal period to the adult age. The pulmonary phospholipid content showed a sharp increase at term from premature low level. At the same time the LPL activity increased markedly showing thereafter a decrease at 1 week of age and increasing thereafter to the adult age. Also the phospholipid content was low at 1 week of age. Thus the pulmonary phospholipid content and LPL activity change in the same way during the development indicating possibly that the LPL by supplying free fatty acids for the phospholipid biosynthesis may be one of the rate-limiting enzymes in the pulmonary surfactant synthesis.

Age Factors↗
PubMed2001

Pre-heparin plasma lipoprotein lipase mass: correlation with intra-abdominal visceral fat accumulation.

OBJECTIVE: To determine how lipoprotein lipase mass in the pre-heparin plasma is affected by body fat distribution, which is known to be closely related to lipid disorder, either directly or through insulin resistance. SUBJECTS: A total of 57 subjects consisting of 50 hyperlipidemic and 7 normolipidemic subjects (age 54 +/- IIy; 31 men, 26 women; body mass index 24+/- 2.5 kg/m2; serum total cholesterol 6.4+/-1.5 mmol/l; triglycerides, 2.4 +/- 1.7 mmol/l; HDL-cholesterol 1.3 +/- 0.5 mmol/l) were enrolled. MEASUREMENTS: We investigated the correlation between pre-heparin plasma LPL mass and intra-abdominal visceral fat area (or subcutaneous fat area) evaluated by computed tomography, and serum lipids and lipoproteins. RESULTS: Pre-heparin plasma LPL mass correlated inversely against intra-abdominal visceral fat area (r = - 0.51, p < 0.0001) and body mass index (r = - 0.46, p = 0.0003), but did not show any significant correlation with subcutaneous fat area. Pre-heparin plasma LPL mass had a positive correlation with serum high density lipoprotein cholesterol (r = 0.45, p = 0.0004) and a negative correlation against serum triglycerides (r = - 0.48, p = 0.0002). CONCLUSIONS: Pre-heparin plasma LPL mass is closely associated with intra-abdominal fat distribution, and the measurement of its value gives useful information concerning metabolic disorder.

Adipose Tissue↗
PubMed1988

Short-term stimulation by insulin of lipoprotein lipase secretion in adipose cells.

The spontaneous secretion of lipoprotein lipase has been examined in adipose cells of mouse Ob17, Ob17SA and 3T3-F442A clonal lines as well as in rat adipose cells in primary culture. Striking differences are observed both in serum-free and serum-supplemented media, rat adipose cells and 3T3-F442A cells being the most active. Insulin from 10(-11) M to 10(-9) M was able to modulate the rate of LPL secretion from 2- to 4-fold. The stimulatory effect of insulin on this process occurred within 30 min in cells treated or not with cycloheximide. It is concluded that insulin is able to modulate the rate of LPL secretion independently of the synthesis of new enzyme molecules on a short-term basis and within a physiological range of concentrations.

Adipose Tissue↗
PubMedDate not supplied

[Determination of the activities of lipoprotein lipase, triacylglycerolipase, monoacylglycerolipase, and tributyrinase in the plasma, myocardium, and cardiac adipose tissue of rabbits].

Fatty emulsion intralipid, activated by rabbit blood plasma, intralipid, micellar emulsion of monooleine and tributyryne emulsion were used, respectively, as substrates for estimation of asctivities of lipoprotein lipase (EC 3.1.1.34), triacyl glycerolipase (EC 3.1.1.3), monoacyl glycerolipase (EC 3.1.1.23) and tributyrynase (EC 3.1.1.13) by modified Dol's method in rabbit heart tissue, heart fatty tissue and blood plasma. Effect of heparin on extraction of lipolytic enzymes from tissues was studied.

Adipose Tissue↗
PubMed1982

On the pH dependency of lipoprotein lipase activity.

The relation between pH and activity for lipoprotein lipase against emulsions of long-chain triacylglycerols has previously been studied in several laboratories and found to be a bell-shaped curve with optimum activity between pH 8 and 9. In contrast, using short-chain triacylglycerols or monoacylglycerols as substrates we had found that the activity rises continuously with pH to at least pH 10.5. This suggested that some factor other than the active site mechanism limited the activity at high pH in traditional assay systems. We, therefore, reinvestigated the activity against long-chain triacylglycerols under conditions where binding of the enzyme to the emulsion droplets and enzyme stability was not limiting. Under these conditions the activity continued to rise from pH 8 to pH 10, and the degree of stimulation by apolipoprotein C-II was found to be the same over the whole range studied (pH 6.5-10.5).

Animals↗
PubMed1994

Recurrent missense mutations at the first and second base of codon Arg243 in human lipoprotein lipase in patients of different ancestries.

Mutations in the lipoprotein lipase (LPL) gene are the most common cause of familial chylomicronemia. Here we define the molecular basis of LPL deficiency in four patients of German, French, Dutch, and Chinese descent. We show that two of the probands of Dutch and Chinese origin have a previously described Arg243His mutation while the patients of German and French descent have a novel Arg243Cys substitution in their LPL gene. Haplotype analysis is in favour of two separate origins for the Arg243Cys substitution which together with the Arg243His mutation would implicate three recurrent mutations involving the first and second nucleotides of the codon encoding Arg243 of the LPL gene. The recurrent mutations affecting the first and second nucleotide of CGC coding for the normal Arg residue are support for the high mutability of CpG dinucleotides within the LPL gene.

Adult↗
PubMed1986

Immunologic and enzymatic comparisons between human and bovine lipoprotein lipase.

Studies were conducted to compare human and bovine lipoprotein lipase (LPL) preparations with regard to immunological cross-reactivity and substrate specificity. LPL was partially purified from human milk. An antiserum against the human LPL preparation was produced in a goat. This antiserum inhibited LPL enzymatic activity in human milk and in human post-heparin plasma. Neither bovine milk nor bovine post-heparin plasma LPL enzymatic activity was inhibited by this antiserum. These findings suggest that there are significant structural differences between the human and bovine enzymes in domains that are involved in enzymatic activity. Human and bovine post-heparin plasma and partially purified preparations of LPL from human and bovine milk were compared with regard to substrate specificity, by comparing their lipolytic activities against triglyceride, cholesteryl esters, and retinyl esters. Only the partially purified bovine milk LPL preparation possessed retinyl palmitate hydrolase activity. The results suggest that this latter activity may be the result of a previously unrecognized contaminant in the commonly used LPL preparations from bovine milk.

Animals↗