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PubMed1992

A G----C change at the donor splice site of intron 1 causes lipoprotein lipase deficiency in a southern-Italian family.

We describe a new case of lipoprotein lipase deficiency in a proband from a Southern-Italian family. Enzyme activity and mass were absent. Amplification and sequencing of individual exons, intron boundaries and the regulatory region revealed only one homozygous G----C transversion at the first nucleotide of intron 1. The single strand conformation polymorphism analysis proved to be a helpful tool for the identification of the single base mutation. Northern hybridization failed to reveal the presence of mature lipoprotein lipase mRNA. The mutation, which destroys the conserved dinucleotide at the junction site of intron 1, causes defective mRNA splicing and it is responsible for the deficiency.

Adult↗
PubMed1993

Overexpression of human lipoprotein lipase in transgenic mice. Resistance to diet-induced hypertriglyceridemia and hypercholesterolemia.

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. To determine the role of LPL in lipoprotein metabolism, we established three transgenic mouse lines overexpressing the human LPL gene; the highest expressor line, which transcribed human LPL mRNA in the heart, skeletal muscles, and adipose tissue, was used in this study. The transgenic mice had 5- and 1.7-fold higher LPL activity in adipose tissue and post-heparin plasma, respectively. Plasma triglyceride levels in transgenic mice were 24.2% of that in control mice, and gel filtration chromatography showed that very low density lipoprotein (VLDL) triglycerides were much reduced in transgenic mice. In the chemical analysis of plasma lipoproteins isolated by ultracentrifugation, we found that LDL particles were cholesterol-rich and HDL2 cholesterol was increased 1.4-fold in transgenic mice as compared to control mice. When we injected 125I-VLDL intravenously into transgenic mice, the clearance of 125I-VLDL and the conversion of VLDL to LDL was markedly enhanced as compared to control mice. Furthermore, the clearance of chylomicrons, estimated by both the fat loading and retinyl palmitate loading tests, was significantly enhanced in transgenic mice. After sucrose feeding, no increase in VLDL was observed in transgenic mice. When fed a high cholesterol diet, the development of hypercholesterolemia was suppressed in transgenic mice. These results suggested that LPL determined not only hydrolysis of triglyceride-rich lipoproteins but also lipolytic conversion, and that overexpression of LPL acted to protect against diet-induced hypertriglyceridemia as well as hypercholesterolemia.

Actins↗
PubMed1978

Relation of plasma high-density lipoprotein cholesterol to lipoprotein-lipase activity in adipose tissue and skeletal muscle of man.

Lipoprotein-lipase activity (LPL) was measured in biopsies of adipose tissue and skeletal muscle of normal human subjects, and the results were related to concentrations of cholesterol and triglycerides in plasma lipoproteins. Adipose-tissue LPL activity was significantly higher in females than in males, whereas no sex difference was observed in skeletal-muscle LPL activity. A highly significant positive correlation was present between the plasma high density lipoprotein (HDL) cholesterol level and LPL activity in adipose tissue (r = +0.66, P less than 0.001) but not between HDL and skeletal-muscle LPL. The results suggest that the activity of LPL in adipose tissue and the rate of catabolism of triglyceride-rich lipoproteins might be one of the factors that determine the concentration of HDL in plasma and at least partly account for the known sex difference in plasma HDL level.

Adipose Tissue↗
PubMed2003

Transgenic mice expressing lipoprotein lipase in adipose tissue. Absence of the proximal 3'-untranslated region causes translational upregulation.

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein and adipocyte metabolism. Defects in LPL can lead to hypertriglyceridemia and the subsequent development of atherosclerosis. The mechanisms of regulation of this enzyme are complex and may occur at multiple levels of gene expression. Because the 3'-untranslated region (UTR) is involved in LPL translational regulation, transgenic mice were generated with adipose tissue expression of an LPL construct either with or without the proximal 3'-UTR and driven by the aP2 promoter. Both transgenic mouse colonies were viable and expressed the transgene, resulting in a 2-fold increase in LPL activity in white adipose tissue. Neither mouse colony exhibited any obvious phenotype in terms of body weight, plasma lipids, glucose, and non-esterified fatty acid levels. In the mice expressing hLPL with an intact 3'-UTR, hLPL mRNA expression approximately paralleled hLPL activity. However in the mice without the proximal 3'-UTR, hLPL mRNA was low in the setting of large amounts of hLPL protein and LPL activity. In previous studies, the 3'-UTR of LPL was critical for the inhibitory effects of constitutively expressed hormones, such as thyroid hormone and catecholamines. Therefore, these data suggest that the absence of the 3'-UTR results in a translationally unrepressed LPL, resulting in a moderate overexpression of adipose LPL activity.

3' Untranslated Regions↗
PubMed2004

Nutritional regulation of lipoprotein lipase in mice.

Tissue-specific regulation of lipoprotein lipase (LPL) has been extensively studied in rats. The mouse is now the most used animal in lipoprotein research, and we have therefore explored the regulation of LPL in this species. In C57 black mice, fed ad libitum adipose tissue LPL activity changed about three-fold with the time of day, indicating a circadian rhythm. The highest activity was at midnight and the lowest activity was at noon. Withdrawal of food did not markedly accelerate the drop of activity that occurred from midnight until noon, but prevented the return of activity that occurred during the evening and early night. When food was returned to mice that had been fasted for 24h, adipose tissue LPL activity rose rapidly and returned to the fed level in 2h. LPL mass in adipose tissue changed less than LPL activity, indicating that regulation is mainly post-translational as previously demonstrated for rats. When transcription was blocked in fasted mice, adipose tissue LPL activity increased, as previously observed in rats. LPL activity in heart was highest early in the light period at 9:00h and lowest at 21:00h. The change was, however, only about 30%. Heparin-releasable LPL activity in heart was 1.8-fold higher in mice fasted for 6h compared to fed controls. We conclude that LPL activity responds to the nutritional state in the same direction and by the same mechanisms in mice as in rats, but the magnitude of the changes are less in mice.

Adipose Tissue↗
PubMedDate not supplied

Serum lipoprotein and lipoprotein lipase in overweight, type II diabetics during and after supplemented fasting.

Poorly controlled, obese, Type II diabetics were studied before, during, and 3 months after a weight reduction program that used supplemented fasting (200 kcal or 0.9 MJ/day). During fasting, the very low density lipoprotein (VLDL) triglycerides (TG) decreased, as did the adipose tissue lipoprotein lipase (AT-LPLA) and skeletal muscle lipoprotein lipase (SM-LPLA) activities. Three months later VLDL TG remained low (-59%), while high density lipoprotein cholesterol was higher (+11%) and blood glucose control improved compared with values on admission. The fractional removal rate (K2) at the i.v. fat tolerance test (IVFTT) and the SM-LPLA were unchanged, while AT-LPLA (expressed per gram of wet weight, but not as whole-body AT-LPLA) increased by 25%. There were no significant correlations between AT-LPLA and the lipoprotein TG concentrations or K2-IVFTT, although there were significant positive correlations between SM-LPLA and K2-IVFtt, both on admission and after body weight stabilization. This may indicate that SM-LPLA is more directly related to the capacity to remove lipoprotein TG, at least in obese diabetic patients. K2-IVFTT was inversely correlated to the VLDL TG and cholesterol concentrations both before and 3 months after fasting. Because both SM-LPLA and K2-IVFTT were unchanged after body weight reduction, the change in VLDL TG may be mainly due to a reduced rate of lipoprotein synthesis.

Adipose Tissue↗
PubMed1972

Enzymic depolymerization of macromolecular heparin as a factor in control of lipoprotein lipase activity.

Macromolecular heparin from rat skin shows poor lipoprotein lipase-releasing activity in vivo and is a potent inhibitor of rat-heart lipoprotein lipase in vitro. Rat-skin heparin is depolymerized by incubation with the 100,000 x g supernatant from a sonicated homogenate of rat small intestine. The depolymerized products, fractionated by gel filtration, range from inhibitors to activators of lipoprotein lipase as molecular size decreases. Depolymerized rat heparin in the same molecular size range as commercial heparin from pig intestinal mucosa has about two-thirds the activity of the commercial preparation, both in vivo and in vitro.

Animals↗
PubMed1989

Release of lipoprotein lipase and hepatic triglyceride lipase in rats by heparin and other sulphated polysaccharides.

The ability of parenteral heparin to release the capillary-bound enzymes lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) into the circulation is shared by several other sulphated polysaccharides. The lipase-releasing activity in rats of two unfractionated heparins has been compared with that of characterised preparations of other glycosaminoglycans and of two partially synthetic polysaccharides. The results suggest that whilst both molecular weight and degree of sulphation are important in determining the potency, there is also some specific structural element associated with the heparin class. The clearance of lipases was also investigated. The half-lives of LPL (29 mins) and of HTGL (36 mins) did not appear to be affected by the nature of the releasing agent.

Animals↗
PubMed1993

Association of lipoprotein lipase gene variation with the physiological components of the insulin-resistance syndrome in the population of the San Luis Valley, Colorado.

OBJECTIVE: To cross-sectionally evaluate the presence of clustering of the insulin-resistance syndrome components. Tests were conducted for association of the HindIII restriction site polymorphism at the lipoprotein lipase locus with clustering of the physiological components of the insulin resistance syndrome. RESEARCH DESIGN AND METHODS: DNA samples of 370 normoglycemic Hispanics and 520 normoglycemic non-Hispanic whites from the San Luis Valley, Colorado, were amplified by the polymerase chain reaction. Lipids and glucose were determined by the standard procedures. Cross-tabulation and chi 2 analysis were used. RESULTS: The insulin-resistance syndrome components (elevated fasting insulin, reduced high-density lipoprotein cholesterol, and elevated triglycerides) appeared together in individuals of this population sample more often than expected by chance. Individuals in the population with the (+/+) lipoprotein lipase-HindIII restriction of fragment-length polymorphism genotype were more likely to have elevated fasting insulin and triglycerides and a reduced high-density lipoprotein-cholesterol level than subjects with the (+/-) genotype (odds ratio = 2.3, 95% confidence interval 1.38-3.98). CONCLUSIONS: As expected from the physiological function of lipoprotein lipase, the primary association of lipoprotein lipase genotypes is with triglyceride and high-density lipoprotein-cholesterol levels. This appears to be the first reported genetic association with the insulin-resistance syndrome and may reflect genotype specific differences in the regulation of lipoprotein lipase by insulin.

Base Sequence↗
PubMed1983

Acute effects of ethanol and its metabolites on plasma lipids and lipoprotein lipase activity.

The effects of ethanol, acetaldehyde, acetate and lactate on lipoprotein lipase (LPL) activity and regulation have been investigated. None of the substances had any direct effect on the enzyme or enzyme-substrate complex. Ethanol and acetate interfered with LPL regulation studied in vitro using rat adipose tissue. Acetate administration to humans did not influence the activity of LPL and hepatic lipase in post-heparin plasma, nor was the intravenous fat tolerance test affected. Ethanol administration markedly increased and prolonged the hyperlipidemia induced by oral triglyceride intake; the effect of acetate was much less pronounced. Thus, acetate does not seem to interfere with LPL regulation in man. The previously described impairment in LPL activity and regulation after ethanol intake is probably mediated by ethanol itself.

Acetates↗
PubMed1989

Inhibition of purified human postheparin lipoprotein lipase by beta-adrenergic blockers in vitro.

We examined the effects of five beta-adrenergic blockers on the hydrolysis of phosphatidylcholine-stabilized triolein particles by purified human postheparin lipoprotein lipase (PHLpL) in order to evaluate the possible role of direct inhibition as a mechanism of drug-induced hypertriglyceridemia. The relative inhibitory potencies were observed in the following order: propranolol much greater than pindolol greater than metoprolol greater than atenolol greater than nadolol. There was a positive correlation between the octanol/water partition coefficients of these agents and their inhibition of lipoprotein lipase, suggesting that hydrophobicity may be one of the major determinants for PHLpL inhibition. The amount of the beta-adrenergic blockers required to produce 50% inhibition of human PHLpL was much greater than that required to inhibit purified bovine lipoprotein lipase.

Adrenergic beta-Antagonists↗
PubMed1996

Tissue-specific regulation of lipoprotein lipase by isoproterenol in normal-weight humans.

Lipoprotein lipase (LPL) is a hydrolytic enzyme, involved in lipoprotein metabolism and nutrient partitioning, that is subject to tissue-specific regulation. Evidence for divergent regulation of the lipase by insulin has been demonstrated, but alterations in the tissue-specific response of LPL to catecholamines has not been studied in humans. The regulation of LPL in gluteal adipose tissue and vastus lateralis muscle by isoproterenol (epinephrine isopropyl homologue) in humans was examined over 2 h in subjects infused with 0 (saline) or 8 or 24 ng.kg-1.min-1 isoproterenol. The infusion of normal saline into control subjects failed to alter adipose tissue or skeletal muscle LPL activity. However, in the saline-infused subjects there was a positive correlation between the percent change in plasma norepinephrine concentrations and the percent change in muscle LPL activity (r = 0.826, P < 0.05). Isoproterenol infusion did not change LPL in either adipose tissue or muscle compared with saline-infused controls, but plasma insulin levels in addition to plasma glucose, free fatty acids, and glycerol were increased. To prevent the isoproterenol-induced hyperinsulinemia, a pancreatic clamp technique was utilized. An increase in muscle LPL was demonstrated (P = 0.037) with no change in adipose tissue LPL. The change in muscle LPL activity after the 2-h infusion correlated with the change in muscle mRNA (P = 0.021). Overall, these studies indicate that in humans the response of LPL to catecholamines is tissue specific with no effect in adipose tissue but a stimulation in skeletal muscle. Endogenous regulation of LPL in muscle by catecholamines could be important in muscle fuel metabolism and could relate to effects of adenosine 3',5'-cyclic monophosphate and/or fatty acids at the level of the LPL gene.

Adipose Tissue↗
PubMed1993

Expression of lipoprotein lipase mRNA and secretion in macrophages isolated from human atherosclerotic aorta.

The expression of lipoprotein lipase (LPL) mRNA and the LPL activity were studied in macrophages (CD14 positive) from human atherosclerotic tissue. Macrophages were isolated after collagenase digestion by immunomagnetic isolation. About 90% of the cells were foam cells with oil red O positive lipid droplets. To analyze the mRNA expression, PCR with specific primers for LPL was used. Arterial macrophages were analyzed directly after isolation and the data showed low expression of LPL mRNA when compared with monocyte-derived macrophages. To induce the expression of LPL mRNA in macrophages, PMA was used. When incubating arterial macrophages with PMA for 24 h we could not detect any increase in LPL mRNA levels. Similarly, the cells secreted very small amounts of LPL even after PMA stimulation. In conclusion, these studies show a very low expression of LPL mRNA in the CD14-positive macrophage-derived foam cells isolated from human atherosclerotic tissue. These data suggest that the CD14-positive cells are a subpopulation of foam cells that express low levels of lipoprotein lipase, and the lipid content could be a major factor for downregulation of LPL. However, the cells were isolated from advanced atherosclerotic lesions, and these findings may not reflect the situation in early fatty streaks.

Aged↗
PubMedDate not supplied

[Effect of qualitatively varied nutrition on the lipoprotein lipase activity in rat tissues].

Isocaloric food rations with a steady protein level, but differing proportions and quality of carbohydrates and fat produce a marked effect on the activity of the lipoprotein lipase in the fat tissue and liver of rats, affecting the blood insulin level to a lesser degree. In investigated tissues a reduced activity of the enzyme was noted to occur by using a ration carrying an excess amount of animal fat and of a diet with saccharose balanced in proportions of carbohydrates and fat. A fat-rich ration with a vegetable oil and a carbohydrate-rich ration with saccharose heighten the activity of the lipoprotein lipase both in the fat tissue and in the liver, but produce an opposite action on the blood insulin concentration. The absence of direct relation between the activity of the enzyme and the blood insulin level indicates that under the effect of food differed by its chemical composition the blood insulin concentration is not a decisive factor in regulating the activity of the lipoprotein lipase in tissues.

Adipose Tissue↗
PubMed1981

Lipoprotein lipase: modification of its kinetic properties by mild tryptic digestion.

Mild tryptic digestion of lipoprotein lipase cleaved its polypeptide chain in the middle, but the pieces were held together by disulphide bonds. The modified enzyme retained its ability to bind to heparin and to anionic detergents and on gel filtration it eluted in a similar position as the native enzyme does. It also retained essentially full activity against soluble substrates. Thus, the overall physico-chemical properties of the enzyme were not markedly changed and its active site remained intact after treatment with trypsin. The activity of the modified enzyme against long-chain acylglycerols and phospholipids was, however, much reduced. With some emulsions, the decreased activity could be ascribed in part to a decreased ability of the modified enzyme to bind to the emulsion droplets. Under these conditions apolipoprotein CII partially restored both binding and activity. With a lysophosphatidylcholine-triacylglycerol emulsion the modified enzyme adsorbed almost completely to the emulsion droplets, but its activity was nonetheless very low. Thus, tryptic cleavage interfered with the ability of the enzyme to become properly orientated at the interface. With this emulsion apolipoprotein CII enhanced the activity of the native enzyme fourfold but the activity of the trypsin-treated enzyme 30-fold, so that the activity of the modified enzyme became almost as high as that of the native enzyme. It is concluded that apolipoprotein CII enhances the activity of lipoprotein lipase by stabilizing an effective orientation/conformation of the enzyme at the interface. This effect became more marked when the ability of the enzyme itself to attain this form had been reduced by tryptic cleavage.

Animals↗
PubMed1995

Lipoprotein lipase mass and activity in plasma and their increase after heparin are separate parameters with different relations to plasma lipoproteins.

Lipoprotein lipase (LPL) activity and mass in plasma and their increase after heparin administration were measured in 61 men who had suffered myocardial infarction before the age of 45 years and in 69 population-based age- and sex-matched control subjects without coronary heart disease to study the relations between these parameters in plasma and their correlations with plasma lipoproteins in subjects with a wide range of lipoprotein and LPL levels. There was a relatively large amount of LPL protein compared with LPL activity in preheparin plasma, indicating that the majority of circulating LPL is catalytically inactive. LPL mass and activity in postheparin plasma (postheparin minus preheparin values) were highly correlated, and the calculated mean specific activity (0.35 mU/ng) was in the range expected for catalytically active LPL. Hence, heparin releases mainly active LPL. The four LPL parameters (mass and activity in plasma and their increase after heparin administration) were not related to each other, except for postheparin plasma LPL mass and activity, and they showed different correlations with plasma lipoprotein lipid concentrations. There was a strong positive correlation between LPL mass in preheparin plasma and the HDL cholesterol level as well as weak negative relations to VLDL triglyceride and cholesterol concentrations in the patients. In contrast, preheparin LPL activity showed no correlation with the HDL cholesterol level but weak positive relations to VLDL triglyceride and cholesterol concentrations in the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Transgenic mice expressing human lipoprotein lipase driven by the mouse metallothionein promoter. A phenotype associated with increased perinatal mortality and reduced plasma very low density lipoprotein of normal size.

We have produced transgenic mice expressing human lipoprotein lipase (LPL) driven by the mouse metallothionein I promoter. We found that integration of the LPL gene construct was associated with a high perinatal mortality. Animals that survived the first 2 weeks of life grew normally afterwards. Compared with controls, transgenic animals had higher post-heparin plasma LPL and tissue LPL activities. Immunoreactive human LPL was detected in their post-heparin plasma but not in controls. Transgenic animals had significantly lower plasma very low density lipoprotein (VLDL) while on a regular laboratory chow. By electron microscopic analysis and nondenaturing polyacrylamide gradient gel electrophoresis, the size and morphology of the plasma VLDL were very similar in transgenic and control animals, which suggests that VLDL particles acted on by the increased tissue LPL in the transgenic animals were mostly taken up by the cell without being released back into circulation. The hypertriglyceridemia and elevated VLDL in response to sucrose feeding were completely abolished in transgenic animals. They also had lower VLDL lipids compared with control animals when they were fed a high-fat, high-cholesterol diet. Feeding the mother of transgenic mice a high-fat diet during pregnancy completely reversed the high perinatal mortality associated with the integrated transgene, which suggests that the deleterious effect of LPL overexpression may be related to the depletion of some essential lipid nutrient.

Animals↗
PubMed1987

Changes in plasma lipoproteins and tissue lipoprotein lipase and salt-resistant lipase activities during spawning in the rainbow trout (Salmo gairdnerii R.).

1. Lipoprotein lipase and salt-resistant lipase activities increased in the ovaries but decreased in the adipose tissue of female trout in the months leading up to spawning. 2. The activity of the plasma cholesterol esterifying enzyme increased significantly immediately prior to spawning. 3. Plasma lipoprotein concentrations decreased during the approach to spawning. 4. These studies suggest that the developing ovaries in the trout receive their nutrients by lipolysis of plasma lipoproteins as well as by vitellogenin uptake; differentiation of the roles of the lipid stores in different tissues is proposed.

Adipose Tissue↗