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PubMed1983

Effect of colchicine on heart lipoprotein lipase.

Changes in heart lipoprotein lipase (LPL) activity provoked by colchicine (0.5 mg/100 g body weight) and heparin (10 IU/100 g body weight) were studied in heart homogenates and serum from rats treated with both drugs or with heparin alone. In addition experiments were carried out in vitro in which the action of colchicine alone and colchicine plus heparin was compared with controls. In vivo experiments showed that colchicine decreased post-heparin release of the enzyme in fed animals, but was incapable of doing so in fasted animals. Accordingly, heart LPL activity, expressed in percentage of control values, did not change in fed animals, but significantly decreased (p less than 0.05) in fasted animals. In the in vitro experiments, colchicine significantly decreased heart LPL activity (p = 0.025) whether or not heparin was present and regardless of the nutritional state of the rats. Apparently, colchicine has two distinct actions on heart LPL activity: a direct one on the enzyme and another mediated by the nutritional state of the animal.

Animals↗
PubMed1991

Structural and functional roles of highly conserved serines in human lipoprotein lipase. Evidence that serine 132 is essential for enzyme catalysis.

The structure of human lipoprotein lipase was recently deduced from its cDNA sequence. It contains 8 serine residues (residues 45, 132, 143, 172, 193, 244, 251, and 363) that are absolutely conserved in both lipoprotein lipase and hepatic lipase across all species studied. The high homology between lipoprotein lipase, hepatic lipase, and pancreatic lipase suggests that the catalytic functions of these enzymes share a common mechanism and that one of the 8 conserved serines in human lipoprotein lipase must play a catalytic role as does serine 152 in the case of pancreatic lipase (Winkler, F. K., D'Arcy, A., and Hunziker, W. Nature 343, 771-774). We expressed wild-type and site-specific mutants of human lipoprotein lipase in COS cells in vitro. We produced two to four substitution mutants involving each of the 8 serines and assayed a total of 22 mutants for both enzyme activity and the amount of immunoreactive enzyme mass produced. Immunoreactive lipase was detected in all cases. With the exception of Ser132, for each of the 8 serine mutants we studied, at least one of several mutants at each position showed detectable enzyme activity. All three substitution mutants at Ser132, Ser----Thr, Ser----Ala, and Ser----Asp, were totally inactive. Ser132 occurs in the consensus sequence Gly-Xaa-Ser-Xaa-Gly present in all serine proteinases and in human pancreatic lipase. The x-ray crystallography structure of human pancreatic lipase suggests that the analogous serine residue in human pancreatic lipase, Ser152, is the nucleophilic residue essential for catalysis. Our biochemical data strongly support the conclusion that Ser132 in human lipoprotein lipase is the crucial residue required for enzyme catalysis. The observed specific activities of the variants involving the other seven highly conserved serines in human lipoprotein lipase are consistent with the interpretation that this enzyme has a three-dimensional structure very similar to that of human pancreatic lipase.

Amino Acid Sequence↗
PubMed1992

Lipoprotein lipase and hepatic lipase activities are differentially regulated in isolated hepatocytes from neonatal rats.

Lipoprotein lipase and hepatic lipase are members of the lipase gene family sharing a high degree of homology in their amino acid sequences and genomic organization. We have recently shown that isolated hepatocytes from neonatal rats express both enzyme activities. We show here that both enzymes are, however, differentially regulated. Our main findings are: (i) fasting induced an increase of the lipoprotein lipase activity but a decrease of the hepatic lipase activity in whole liver, being in both cases the vascular (heparin-releasable) compartment responsible for these variations. (ii) In isolated hepatocytes, secretion of lipoprotein lipase activity was increased by adrenaline, dexamethasone and glucagon but was not affected by epidermal growth factor, insulin or triiodothyronine. On the contrary, secretion of hepatic lipase activity was decreased by adrenaline but was not affected by other hormones. (iii) The effect of adrenaline on lipoprotein lipase activity appeared to involve beta-adrenergic receptors, but stimulation of both beta- and alpha 1-receptors seemed to be required for the effect of this hormone on hepatic lipase activity. And (iv), increased secretion of lipoprotein lipase activity was only observed after 3 h of incubation with adrenaline and was blocked by cycloheximide. On the contrary, decreased secretion of hepatic lipase activity was already significant after 90 min of incubation and was not blocked by cycloheximide. We suggest that not only synthesis of both enzymes, but also the posttranslational processing, are under separate control in the neonatal rat liver.

Animals↗
PubMed1992

Exercise training has a heparin-like effect on lipoprotein lipase activity in muscle.

Lipoprotein lipase (LPL) is anchored with high affinity to heparan sulphate proteoglycans on the luminal surface of the capillary endothelium. The levels of pre-heparin perfusate LPL activity increased from 16 +/- 1 to 145 +/- 6 U/hindlimb (nine-fold increase) in hindlimb muscle of exercise-trained rats measured immediately after the last bout of work. At the same time, post-heparin perfusate LPL activity decreased from 63 +/- 2 to 13 +/- 1 U/hindlimb (p less than 0.001). These results provide evidence that exercise-training has a heparin-like effect on capillary-bound LPL. The total amount of LPL (i.e., pre-heparin perfusate plus post-heparin perfusate) was twofold greater in the hindlimb of the trained animals versus the controls. The effect of exercise on muscle LPL activity appears to last for as long as 5 days after cessation of exercise. Serum triglycerides were reduced 38% and plasma free fatty acids increased fourfold. These results provide evidence that training increases the capacity to remove triglycerides from circulation.

Adipose Tissue↗
PubMed1994

Lipoprotein lipase domain function.

Human lipoprotein lipase (LPL) monomer consists of two domains, a larger NH2-terminal domain that contains catalytic residues and a smaller COOH-terminal domain that modulates substrate specificity and is a major determinant of heparin binding. Analyses of NH2-terminal domain function were performed after site-directed mutagenesis of the putative active-site serine residue, while COOH-terminal domain function was assessed following reaction with a monoclonal antibody. The native enzyme and mutant LPL in which serine 132 was replaced with alanine, cysteine, or glycine were transiently expressed in COS-7 cells. Mutant proteins were synthesized and secreted at levels comparable to native LPL; however, none of the mutants retained enzymatic activity. The mutant with alanine replacing serine 132 was purified and shown to be inactive with both esterase and lipase substrates; however, binding to a 1,2-didodecanoyl-sn-glycero-3-phosphatidylcholine monolayer was comparable to native LPL. These results are consistent with a catalytic, and not a lipid binding, role for serine 132. To investigate the function of the smaller COOH-terminal domain, LPL lipolytic and esterolytic activities as well as heparin binding properties were determined after reaction with a monoclonal antibody specific for this domain. Lipolytic activity was inhibited by the monoclonal antibody, whereas esterolytic activity was only marginally affected, indicating that the LPL COOH-terminal domain is required for lipolysis, perhaps by promoting interaction with insoluble substrates. Also, the affinity of antibody-reacted LPL for heparin was not significantly different from that of LPL alone, suggesting that (i) the heparin-binding site is physically distinct from the COOH-terminal domain region required for lipolysis and (ii) binding of antibody did not cause dimer dissociation. A model is proposed for the two LPL domains fulfilling different roles in the lipolytic process.

Animals↗
PubMed1996

Diurnal rhythms and effects of fasting and refeeding on rat adipose tissue lipoprotein lipase.

The activity of lipoprotein lipase (LPL) in adipose tissue is modulated by changes in the nutritional status. We have measured LPL activity, mass, and mRNA levels in rat adipose tissue during normal feeding cycles, during short- and long-term fasting, and during refeeding after fasting. LPL activity displayed a diurnal rhythm. The activity was highest during the night and early morning, decreased to a minimum during the early afternoon, and then increased again. These changes corresponded to the feeding pattern. The increases and/or decreases resulted from changes in LPL synthetic rate compounded by posttranslational mechanisms. During short-term fasting, LPL specific activity decreased to < 30% of control. The specific activity was restored within 4 h by refeeding. On longer fasting, LPL mRNA decreased. This became significant from 36 h. On refeeding, it took 12 h to restore the mRNA levels, whereas tissue LPL activity and mass could not be fully restored by 36 h of refeeding. These data show that LPL activity during short-term fasting is regulated posttranscriptionally, which allows for quick upregulation after refeeding. On longer fasting, other mechanisms affecting LPL transcription and synthesis come into play, and upregulation after refeeding is slowed down.

Adipose Tissue↗
PubMed1990

Synthesis and regulation of lipoprotein lipase in the hippocampus.

Lipoprotein lipase (LPL) expression was determined in adult rat hippocampus and compared to enzyme expression in other brain regions. Hippocampus LPL mRNA levels were at least 2.5-fold higher than those detected in the cerebral cortex, cerebellum, and remaining brain regions. Enzyme mass and activity levels in the hippocampus were also increased to a similar degree. De novo synthesis of LPL in the hippocampus was confirmed by [35S]methionine-labeling of the tissue and identification of a 57 kDa protein obtained by immunoprecipitation. Addition of an excess amount of bovine LPL completely prevented the immunoprecipitation of this protein. The effect of nutritional modulations on brain LPL activity was determined after a 12-h fast. While no significant changes were observed in other regions of the brain, hippocampus LPL activity in fasted rats increased by 60% compared to the fed control group. Simultaneously, fasting reduced adipose LPL activity by 60%. Intraperitoneal injection of ACTH over a 5-day period had no effect on hippocampus LPL activity, while adipose LPL levels increased 2.3-fold and heart LPL levels decreased 1.4-fold. We conclude that LPL is synthesized, active and regulated in a tissue-specific manner in the adult rat hippocampus.

Adipose Tissue↗
PubMed2006

Enhanced apoB48 metabolism in lipoprotein lipase X447 homozygotes.

RATIONALE: Lipoprotein lipase (LPL) X447 homozygotes are characterized by enhanced conversion of TRL apoB100. Here, we set out to investigate whether this LPL variant is also associated with enhanced apoB48 clearance. Therefore, we evaluated apoB48 kinetics in X447 homozygotes in the fed state by infusion of isotope L-[1-(13)C]-valine and subsequent compartmental modeling. METHODS AND RESULTS: ApoB48 metabolism was assessed in five X447 homozygotes (X/X genotype) and five S447 homozygotes (S/S genotype). Subjects were continuously fed and received infusion of stable isotope L-[1-(13)C]-valine. Results were analyzed by SAAM II modeling. Fasting (2.4-fold, p=0.02) as well as non-fasting (1.6-fold, p=0.09) apoB48 concentration was increased in the X447 homozygotes compared to S447 homozygotes. In addition, the X447 homozygotes exhibited a 1.7-fold higher apoB48 poolsize (p=0.04). Interestingly, apoB48 fractional catabolic rate (FCR) was 1.9-fold higher (p=0.007) and apoB48 synthesis was more than two-fold higher (p=0.006) in the X447 homozygotes compared to S447 homozygotes. CONCLUSION: In the present study, we show that X447 homozygotes exhibit enhanced apoB48 clearance. Previously, these homozygotes were shown to present with enhanced apoB100 TRL conversion. Combined, this LPLS447X gain of function variant affects apoB48 as well as apoB100 TRL metabolism.

Apolipoprotein B-48↗
PubMed1989

Effect of marginal zinc deficiency on lipoprotein lipase activities in postheparin plasma, skeletal muscle and adipose tissues in the rat.

The activities of lipoprotein lipase in postheparin plasma, retroperitoneal adipose and gastrocnemius muscle tissues were determined in the rats fed 2.8 ppm of dietary zinc for eight weeks, as compared with pair-fed and ad libitum-fed rats given 30.8 ppm of zinc. The postheparin lipoprotein lipase activity, as determined by using a lipid emulsion labeled with [3H]triolein as the substrate, was significantly lower in the first group of rats, relative to that in the second and third groups. Tissue lipoprotein lipase activities were compared using the lipid emulsion and activator serum obtained from the zinc-deficient rats and the ad libitum-fed rats. The activator sera were devoid of very low density and low density lipoproteins, but enriched in high density lipoproteins. Muscle lipoprotein lipase activities were significantly lower when assayed with the activator serum from the zinc-deficient compared with the activities determined with the activator serum from the ad libitum-fed. Similarly, muscle lipoprotein lipase activities were lower in all groups when [3H]-triolein-labeled chylomicrons from the zinc-deficient were used as the substrate, compared with the activities determined using the chylomicrons from the ad libitum-fed. Lipoprotein lipase activities in the adipose tissues were not affected by the different sources of the activator sera and chylomicrons. The results strongly suggest that the decrease in postheparin lipoprotein lipase activity in zinc deficiency is not due to changes in tissue lipoprotein lipase enzyme per se, but to compositional alterations in chylomicrons and high density lipoprotein, particularly, with regard to C apolipoproteins, modulators of lipoprotein lipase activity.

Adipose Tissue↗
PubMed1991

Transport of lipoprotein lipase across endothelial cells.

Lipoprotein lipase (LPL), synthesized in muscle and fat, hydrolyzes plasma triglycerides primarily while bound to luminal endothelial cell surfaces. To obtain information about the movement of LPL from the basal to the luminal endothelial cell surface, we studied the transport of purified bovine milk LPL across bovine aortic endothelial cell monolayers. 125I-labeled LPL (125I-LPL) added to the basal surface of the monolayers was detected on the apical side of the cells in two compartments: (i) in the medium of the upper chamber, and (ii) bound to the apical cell surface. The amount of 125I-LPL on the cell surface, but not in the medium, reached saturation with time and LPL dose. Catalytically active LPL was transported to the apical surface but very little LPL activity appeared in the medium. Heparinase treatment of the basal cell surface and addition of dextran sulfate (0.15 microM) to the lower chamber decreased the amount of 125I-LPL appearing on the apical surface. Similarly, the presence of increasing molar ratios of oleic acid/bovine serum albumin at the basal surface decreased the transport of active LPL across the monolayer. Thus, a saturable transport system, which requires heparan sulfate proteoglycans and is inhibited by high concentrations of free fatty acids on the basal side of the cells, appears to exist for passage of enzymatically active LPL across endothelial cells. We postulate that regulation of LPL transport to the endothelial luminal surface modulates the physiologically active pool of LPL in vivo.

Animals↗
PubMed2001

Structure-function analysis of D9N and N291S mutations in human lipoprotein lipase using molecular modelling.

Lipoprotein lipase (LPL) plays a central role in lipid metabolism. The D9N and N291S mutations in the LPL gene are associated with elevated triglyceride and decreased HDL-cholesterol levels. Published in vitro expression studies suggest that these two mutations are associated with reduced LPL enzymatic activity. We sought to gain further insight on the impact of these two mutations on the LPL structure and function by molecular modelling techniques. Homology modelling was used to develop a three-dimensional (3D) structure of LPL from human pancreatic lipase. Two separate LPL models for the D9N and N291S substitutions were constructed and compared with the wild type LPL for differences in hydrophobicity, atomic burial, hydrogen bond pattern, and atomic mobility. In comparison to the wild type model, the 9N model was associated with significantly increased atomic mobility of its neighboring residues, but the catalytic site was not affected. The region near residue 9 in the upper part of the N-domain was considered a candidate site for protein-protein interaction. In the N291S model, alterations in H-bonds and constrained atomic mobility were among conformational changes in the region where the substitution had occurred. These are hypothesized to cause an increase in the rate of dissociation in LPL dimerization, subsequently affecting the LPL enzymatic activity. We also modelled the C-domain of apoCII, the obligatory cofactor of LPL, from 2D NMR data and docked the model with LPL to explore their interaction site. These docking experiments suggest that the C-domain of apoCII interacts with the interface of N- and C-domains of LPL and part of the lid structure that covers the catalytic site. In summary, we provide molecular modelling data on two well-known mutations in the LPL gene to help explain the published in vitro expression findings and propose a possible LPL-apoCII interaction site. Our data indicate that molecular modelling of LPL mutations could provide a valuable tool to understand the effects of a mutation on the structure-function of this important enzyme.

Amino Acid Sequence↗
PubMed1981

Lipoprotein lipase and monoacylglycerol lipase activities during maturation of ob17 preadipocytes.

Lipoprotein lipase and monoacylglycerol lipase activities of developing ob17 preadipocytes were assayed through the selective inhibition of the former activity by 0.4% Triton X-100. After confluence both enzymes rose tao a peak activity around 13--15 days which was enhanced in insulin-treated cells. Inclusion of differentiation-blocking agents (bromodeoxyuridine, prostaglandin F2 alpha and bovine retinal extract) in the culture medium led in both enzymes to levels similar to those obtained in exponentially growing cells, in contrast to unspecific monoester hydrolase. Marked changes in the relative proportion of released to intracellular lipoprotein lipase activities were observed during adipose conversion. Our studies indicate that lipoprotein lipase and monoacylglycerol lipase are integral part of the program of differentiation of adipose cells.

Adipose Tissue↗
PubMed1981

Lipoprotein lipase activity in adipose tissue of spontaneously hyperlipidemic rats.

The lipoprotein lipase activity in adipose tissue of Sprague-Dawley rats 1, 4, 9 and 15 months of age, was investigated. The study revealed that a significant inverse relationship exists between serum triglyceride level and lipoprotein lipase activity in epididymal fat pad. Thus, the lipoprotein lipase activity in 1 and 15 months old rats are on the average 5.3 and 1.1 nkat/g wet weight, respectively, simultaneously as serum triglyceride level increase from 0.74 mmol/l to 3.51 mmol/l, respectively. It is suggested that impaired removal of very low density lipoproteins is one possible explanation of the enhanced levels of this lipoproteins in the old rat. The lipase activity investigated had the characteristic properties of lipoprotein lipase, i.e. it was activated by the addition of serum, inhibited by high ionic strength and varied with the nutritional state. However, it could not be exclude that monoacylglycerol lipase present in epididymal fat pad also decreased with age. The possible connection between the age-related reduction of lipoprotein lipase activity in epididymal fat pad and the age-related gomerulonephritis found in these rats is discussed.

Adipose Tissue↗
PubMed1981

Reciprocal changes, caused by insulin and glucagon, of adipose tissue lipoprotein lipase in rats in vitro.

Effects of insulin and glucagon on lipoprotein lipase activity in rat adipose tissue were studied in vitro. Adipose tissue from normal or streptozotocin-diabetic rats was incubated in Krebs-Ringer bicarbonate buffer for 60 min at 38 degrees C in the presence of heparin and lipoprotein lipase released from the tissue into the incubation medium was measured. Diabetic rats showed markedly low activities of adipose tissue lipoprotein lipase. Insulin (500 microU/ml) increased lipoprotein lipase activity in adipose tissue from diabetic rats. Glucagon (500 pg/ml), on the other hand, decreased the enzyme activity in normal rat adipose tissue. The results indicate that insulin and glucagon cause reciprocal changes of lipoprotein lipase activity in rat adipose tissue.

Adipose Tissue↗
PubMed1986

The effects of oral agent or insulin treatments on the plasma lipoproteins and the plasma lipoprotein lipase activator in diabetic patients.

The structure and the metabolism of plasma lipoproteins are altered in diabetes mellitus. Insulin or oral agent treatments affect the lipoprotein metabolism in addition to improving hyperglycemia. However, it is not clear whether the alterations seen in lipoproteins during treatment are related to the degree of diabetic control or to the mode of diabetic treatment. The effects of insulin or oral agent treatments on the plasma lipoproteins and lipoprotein lipase activator were compared in a strictly defined non-obese, non-insulin dependent diabetic patient. Both treatment groups had similar plasma triglyceride, total cholesterol, low and high density lipoprotein cholesterol, and lipoprotein lipase activator levels. Lipoprotein lipase activator contents of the very low density lipoproteins correlated positively with their triglyceride (r = 0.803 in insulin, r = 0.828 in oral agent treated patients) and protein (r = 0.713 in insulin, r = 0.862 in oral agent treated patients) contents. The findings of this study indicated that plasma lipid levels, very low density lipoprotein compositions, and lipoprotein lipase activator contents were not significantly different in non-obese, non-insulin dependent diabetic patients treated with either oral hypoglycemic agents or insulin.

Administration, Oral↗
PubMed1989

Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases.

Lipoprotein lipase is an important regulator of lipid and lipoprotein metabolism. It also contributes to the lipid and energy metabolism of different tissues in varying ways. Although the synthesis, manner of secretion, and mechanism of endothelial binding of lipoprotein lipase appear similar in all tissues, the factors that control gene expression and posttranslational events related to processing vary from tissue to tissue. The actual molecular events that determine this tissue specificity are not yet understood. In the future, however, it may be possible to stimulate or inhibit the activity of lipoprotein lipase in specific tissues and to alter metabolic processes so as to improve the quality and length of life in patients with metabolic diseases such as hypertriglyceridemia, HDL2 deficiency, and obesity.

Humans↗
PubMed1979

Insulin-independent diabetes: a defect in the activity of lipoprotein lipase in adipose tissue.

The activity of lipoprotein lipase (E.C.3.1.1.3.) has been measured in adipose tissue from insulin-independent diabetics with hypertriglyceridaemia, non-diabetics with hypertriglyceridaemia and control patients, all of whom were obese. Although all groups showed an increase of plasma insulin after oral glucose, both the diabetic and nondiabetic hypertriglyceridaemics had impaired activities of lipoprotein lipase in adipose tissue compared to the obese normals (p less than 0.02, p less than 0.03, respectively). A course of insulin therapy (20 u.o.d.) for one week increased the activity of lipoprotein lipase extracted from adipose tissue, lowered plasma triglycerides and improved triglyceride clearance from plasma in a group of diabetics with hypertriglyceridaemia (mean plasma triglyceride 8.7 mmol/l). Our results suggest that a feature in the development of insulin resistance in adult diabetics may be a failure of maintenance of key intracellular enzyme activities involved in lipid metabolism.

Adipose Tissue↗