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PubMed1977

Lipoprotein lipase cofactor activity of a carboxyl-terminal peptide of apolipoprotein C-II.

Apolipoprotein C-II (apoC-II) is a small protein found associated with the plasma lipoproteins. It serves a unique function in the activation of the enzyme lipoprotein lipase (triacylglycerol acyl-hydrolase, EC 3.1.1.3). ApoC-II contains a single arginine residue, permitting tryptic cleavage into two peptides after succinylation of the native protein. The succinylated amino-terminal peptide, approximately 50 residues, did not activate lipoprotein lipase. The succinylated carboxyl-terminal peptide, about 29 residues, had significant cofactor activity. Relative to native apoC-II, the maximal activation observed with the succinylated carboxyl-terminal peptide was 50% lower and the concentration required for half-maximal activity was approximately 10 times higher. Mixtures of the carboxyl- and amino-terminal peptides had no more activity than the carboxyl-terminal peptide alone. Localization of functional properties to the carboxyl region is a feature also common to apolipoproteins C-III, A-II, and A-I.

Amino Acid Sequence↗
PubMed2002

Lipoprotein lipase in the arterial wall: linking LDL to the arterial extracellular matrix and much more.

For low density lipoprotein (LDL) particles to be atherogenic, increasing evidence indicates that their residence time in the arterial intima must be sufficient to allow their modification into forms capable of triggering extracellular and intracellular lipid accumulation. Recent reports have confirmed the longstanding hypothesis that the major determinant(s) of initial LDL retention in the preatherosclerotic arterial intima is the proteoglycans. However, once the initial atherosclerotic lesions have formed, a shift to retention facilitated by macrophage-derived lipoprotein lipase (LPL) appears, leading to the progression of the lesions. Here, we review recent findings on the mechanisms enabling LPL to promote LDL retention and extracellular lipid accumulation in the arterial intima, and we describe the structures in the extracellular matrix that are held to be important in this process. Finally, the potentially harmful consequences of LDL linking by LPL and of other LPL actions in the arterial intima are briefly reviewed.

Animals↗
PubMed2001

Heparin-binding defective lipoprotein lipase is unstable and causes abnormalities in lipid delivery to tissues.

Lipoprotein lipase (LpL) binding to heparan sulfate proteoglycans (HSPGs) is hypothesized to stabilize the enzyme, localize LpL in specific capillary beds, and route lipoprotein lipids to the underlying tissues. To test these hypotheses in vivo, we created mice expressing a human LpL minigene (hLpL(HBM)) carrying a mutated heparin-binding site. Three basic amino acids in the carboxyl terminal region of LpL were mutated, yielding an active enzyme with reduced heparin binding. Mice expressing hLpL(HBM) accumulated inactive human LpL (hLpL) protein in preheparin blood. hLpL(HBM) rapidly lost activity during a 37 degrees C incubation, confirming a requirement for heparin binding to stabilize LPL: Nevertheless, expression of hLpL(HBM) prevented the neonatal demise of LpL knockout mice. On the LpL-deficient background hLpL(HBM) expression led to defective targeting of lipids to tissues. Compared with mice expressing native hLpL in the muscle, hLpL(HBM) transgenic mice had increased postprandial FFAs, decreased lipid uptake in muscle tissue, and increased lipid uptake in kidneys. Thus, heparin association is required for LpL stability and normal physiologic functions. These experiments confirm in vivo that association with HSPGs can provide a means to maintain proteins in their stable conformations and to anchor them at sites where their activity is required.

Amino Acids, Diamino↗
PubMed1998

Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin- and rapamycin-sensitive pathways.

Lipoprotein lipase (LPL) hydrolyzes the triacylglycerol component of circulating lipoprotein particles, mediating the uptake of fatty acids into adipose tissue and muscle. Insulin is the principal factor responsible for regulating LPL activity in adipose tissue, yet the mechanisms whereby insulin controls LPL expression are unknown. The current studies used wortmannin, a specific inhibitor of phosphatidylinositol (PI) 3-kinase, and rapamycin, a specific inhibitor of activation of phosphoprotein 70 ribosomal protein S6 kinase (p70s6k), to explore some of the components of the insulin signaling pathway controlling LPL activity in adipose cells. Preincubation of isolated rat adipose cells with wortmannin completely abrogated the stimulation of LPL activity by insulin, while preincubation with rapamycin caused approximately a 60% inhibition of insulin-stimulated LPL activity. Thus, the current studies show that the regulation of adipose tissue LPL by insulin is mediated via a wortmannin-sensitive pathway, most likely PI 3-kinase, and that a rapamycin-sensitive pathway, most likely p705s6k, constitutes an important downstream component in the insulin signaling pathway through which LPL is regulated.

Adipocytes↗
PubMed1979

Adipose tissue lipoprotein lipase activity in type III hyperlipoproteinemia.

An impairment in the catabolism of chylomicron and very low density lipoprotein remnants appears to cause the lipid abnormalities in type III hyperlipoproteinemia. A reduction in the activity of lipoprotein lipase (LPL) has been suggested as the catabolic defect. Results in this study indicate that the activity of adipose tissue LPL measured in the fasted and fed states are in the normal range in type III hyperlipoproteinemia (fasted: type III = 2.7 +/- 1.8 mU/10(6) cells, N = 8; normals = 3.4 +/- 2.5, N = 23, p, not significant; fed: type III = 3.6 +/- 2.1, N = 7; normals = 4.8 +/- 1.8, N = 12, p, not significant). This suggests that perhaps another mechanism, such as the interaction between LPL and its lipid substrate, is abnormal, or that the activity of LPL derived from another tissue source is deficient.

Adipose Tissue↗
PubMed1960

Inhibition of lipoprotein lipase activity following injection of pituitary extracts into rabbits.

Rabbits given a single subcutaneous injection of an alkaline extract of hog, bovine, or human anterior pituitary glands developed marked hyperlipemia within 12 to 24 hours. The injections in some instances were followed by sickening and death of the animal, though no anatomical changes responsible for these consequences could be determined. No such sequelae were observed in animals given much larger injections of comparable extracts made from other tissues. An inhibitor to lipoprotein lipase appeared regularly in the serum of the injected animals in association with the hyperlipemia. The injection of heparin into such animals failed to result in the elaboration of clearing factor, and serum from these animals inhibited in vitro the hydrolysis of lipid emulsions by active lipoprotein lipase obtained from normal rabbits or human beings. The inhibitor was produced only in vitro by the pituitary extracts. It did not antagonize the anticoagulant action of heparin, and is probably a lipoprotein.

Animals↗
PubMed1997

Nascent very-low-density lipoprotein triacylglycerol hydrolysis by lipoprotein lipase is inhibited by apolipoprotein E in a dose-dependent manner.

In the present study it was investigated whether apolipoprotein (apoE) can inhibit the lipoprotein lipase (LPL)-mediated hydrolysis of very-low-density-lipoprotein (VLDL) triacylglycerols (TAGs). Previous studies have suggested such an inhibitory role for apoE by using as a substrate for LPL either plasma VLDL or artificial TAG emulsions. To mimic the in vivo situation more fully, we decided to investigate the effect of apoE on the LPL-mediated TAG hydrolysis by using VLDL from apoE-deficient mice that had been enriched with increasing amounts of apoE. Furthermore, since plasma VLDL isolated from apoE-deficient mice was relatively poor in TAGs and strongly enriched in cholesterol as compared with VLDL from wild-type mice, we used nascent VLDL obtained by liver perfusions. Nascent VLDL (d<1. 006) isolated from the perfusate of the apoE-deficient mouse liver was rich in TAGs. Addition of increasing amounts of apoE to apoE-deficient nascent VLDL effectively decreased TAG lipolysis as compared with that of apoE-deficient nascent VLDL without the addition of apoE (63.1+/-6.3 and 20.8+/-1.8% of the control value at 2.7 microg and 29.6 microg of apoE/mg of TAG added respectively). Since, in vivo, LPL is attached to heparan sulphate proteoglycans (HSPG) at the endothelial matrix, we also performed lipolysis assays with LPL bound to HSPG in order to preserve the interaction of the lipoprotein particle with the HSPG-LPL complex. In this lipolysis system a concentration-dependent decrease in the TAG lipolysis was also observed with increasing amounts of apoE on nascent VLDL, although to a lesser extent than with LPL in solution (72.3+/-3.6% and 56.6+/-1.7% of control value at 2.7 microg and 29.6 microg of apoE/mg TAGs added respectively). In conclusion, the enrichment of the VLDL particle with apoE decreases its suitability as a substrate for LPL in a dose-dependent manner.

Animals↗
PubMed1998

Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia.

Lipoprotein lipase (LPL), the rate-limiting enzyme in triglyceride hydrolysis, is normally not expressed in the liver of adult humans and animals. However, liver LPL is found in the perinatal period, and in adults it can be induced by cytokines. To study the metabolic consequences of liver LPL expression, transgenic mice producing human LPL specifically in the liver were generated and crossed onto the LPL knockout (LPL0) background. LPL expression exclusively in liver rescued LPL0 mice from neonatal death. The mice developed a severe cachexia during high fat suckling, but caught up in weight after switching to a chow diet. At 18 h of age, compared with LPL0 mice, liver-only LPL-expressing mice had equally elevated triglycerides (10,700 vs. 14,800 mg/dl, P = NS), increased plasma ketones (4.3 vs. 1.7 mg/dl, P < 0.05) and glucose (28 vs. 15 mg/dl, P < 0.05), and excessive amounts of intracellular liver lipid droplets. Adult mice expressing LPL exclusively in liver had slower VLDL turnover than wild-type mice, but greater VLDL mass clearance, increased VLDL triglyceride production, and three- to fourfold more plasma ketones. In summary, it appears that liver LPL shunts circulating triglycerides to the liver, which results in a futile cycle of enhanced VLDL production and increased ketone production, and subsequently spares glucose. This may be important to sustain brain and muscle function at times of metabolic stress with limited glucose availability.

Age Factors↗
PubMed2003

Genetic study of common variants at the Apo E, Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes and coronary artery disease (CAD): variation in LIPC gene associates with clinical outcomes in patients with established CAD.

BACKGROUND: Current evidence demonstrates that positive family history and several alterations in lipid metabolism are all important risk factors for coronary artery disease (CAD). All lipid abnormalities themselves have genetic determinants. Thus, objective of this study was to determine whether 6 genetic variants potentially related to altered lipid metabolism were associated with CAD and with lipid abnormalities in an Italian population. These genetic variables were: apolipoprotein E (Apo E), Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and the hepatic lipase (LIPC) genes. Furthermore, an 8 years prospective analysis of clinical cardiovascular events was related to the various genetic markers. METHODS: 102 subjects with established coronary artery disease and 104 unrelated normal subjects were studied. CAD Patients were followed up for 8 years, and clinical CAD outcomes (a second coronary angioplasty (PTCA), myocardial infarction, coronary artery by-pass graft (CABG), cardiovascular deaths), available from 60 subjects, were related to the genetic variants by multiple regression analysis. Results. Of the six lipid loci studied (for a total of 11 polymorphisms) only the apolipoprotein E, Apo B and LIPC polymorphisms distinguished between case and controls. However, multivariate analysis accounting for clinical and metabolic predictors of CAD showed that only the ApoB Xba1 and ApoE4 polymorphism associated with CAD in this Italian population. When lipid parameters were related to genotypes, the ApoE, ApoB, and LIPC gene polymorphisms were associated to various markers of dyslipidaemia in the CAD patients, confirming previous reports. When the occurrence of a second cardiovascular event was related to genotypes, an independent role was observed for the LIPC gene T202T variant. CONCLUSIONS: variation in LIPC (hepatic lipase) gene associates with clinical outcomes in Italian patients with established CAD. Further studies on the LIPC gene in CAD patients are warranted, in particular looking at the possible influences on clinical outcomes.

Apolipoprotein A-I↗
PubMed1977

The activation of lipoprotein lipase by lipase co-protein (apo C-2).

Kinetic analysis of activation of lipoprotein lipase by apo C-2 indicates that the lipase co-protein increase the rate of lipolysis by adsorption to enzyme at the lipid interface, with formation of a 1:1 molar complex, whose dissociation constant in the presence of triglyceride substrate is about 3 X 10(-13) moles cm-3. Activation by apo C-2, like that by the entire lipoprotein apoprotein moiety (Fielding and Fielding, 1976) is reversible by inorganic salts and the dependence of activation on medium ion-pair activity supports the concept that such inhibition is mediated through a single specific anion-binding site of the lipase co-protein.

Apolipoproteins↗
PubMed1992

Lipoprotein lipase is synthesized by macrophage-derived foam cells in human coronary atherosclerotic plaques.

Lipoprotein lipase (LPL), hydrolyzes the core triglycerides of lipoproteins, thereby playing a role in their maturation. LPL may be important in the metabolic pathways that lead to atherosclerosis, since it is secreted in vitro by both of the predominant cell types of the atherosclerotic plaque, i.e., macrophages and smooth muscle cells. Because of uncertainty concerning the primary cellular source of LPL in atherosclerotic lesions, in situ hybridization assays for LPL mRNA were performed on 12 coronary arteries obtained from six cardiac allograft recipients. Macrophages and smooth muscle cells were identified on adjacent sections with cell-specific antibodies and foam cells were identified morphologically. LPL protein was localized using a polyclonal antibody. LPL mRNA was produced by a proportion of plaque macrophages, particularly macrophage-derived foam cells, but was not detected in association with any intimal or medial smooth muscle cells. These findings were confirmed by combined immunocytochemistry and in situ hybridization on the same tissue sections. LPL protein was detected in association with macrophage-derived foam cells, endothelial cells, adventitial adipocytes, and medial smooth muscle cells, and, to a lesser extent, in intimal smooth muscle cells and media underlying well-developed plaque. These results indicate that macrophage-derived foam cells are the primary source of LPL in atherosclerotic plaques and are consistent with a role for LPL in the pathogenesis of atherosclerosis.

Arteriosclerosis↗
PubMed1987

Effects of dietary saturated and polyunsaturated fat on lipoprotein lipase and hepatic triglyceride lipase activity.

The effects of saturated and polyunsaturated dietary fat on the lipolytic activity of post-heparin plasma, lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) were studied in the rat. The lipolytic activity was studied from 0 to 60 min using labelled chylomicrons as the substrate. Triacylglycerol hydrolysis rate was higher for the plasma of rats fed high fat diets (14% fat by weight). Chylomicrons of rats fed saturated or unsaturated fats were hydrolyzed at the same rate within the first 15 min but afterwards hydrolysis of chylomicrons of rats fed saturated fat was slower. The activities of LPL and HTGL were increased by high fat diets. Unsaturated fat increased more LPL activity than saturated fat conversely, HTGL activity was enhanced more by saturated fat than by unsaturated fat.

Animals↗
PubMed1995

Glycohemoglobin levels relate to the response of adipose tissue lipoprotein lipase to insulin/glucose in obese non-insulin-dependent diabetes mellitus.

Adipose tissue lipoprotein lipase (ATLPL) is responsible for the provision of lipoprotein-derived fatty acids to adipocytes for storage as triglycerides. Fasting ATLPL has been shown to be decreased in non-insulin-dependent diabetes mellitus (NIDDM), an insulin-resistant state. Medically uncomplicated obesity, another state of relative insulin resistance, is associated with decreased stimulation of the enzyme in response to metabolic stimuli. It was therefore hypothesized that the increased insulin resistance of NIDDM would result in an even greater defect in the response of ATLPL to insulin/glucose. Gluteal adipose tissue biopsies were performed in 13 premenopausal obese women with NIDDM, before and after 6 hours of intravenous insulin and glucose. Metabolic data from these studies were then compared with those obtained from 26 nondiabetic obese women of similar age, weight, and fasting insulin concentration (obese controls [OBC]). As expected, fasting gluteal ATLPL activity was lower in the NIDDM group than in OBC (3.7 +/- 0.9 v 11.1 +/- 1.6 nmol free fatty acids [FFA]/min/10(6) cells, P = .0003). The change in ATLPL activity (delta ATLPL) in response to a 6-hour insulin/glucose infusion was not statistically different between the two groups (2.2 +/- 1.1 v 4.7 +/- 1.2, P = .114). However, in NIDDM subjects there was a strong positive relationship between delta ATLPL and glycohemoglobin (GHb) level (r = .883, P = .0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1992

Lipoprotein lipase in plasma after an oral fat load: relation to free fatty acids.

Lipoprotein lipase (LPL) releases fatty acids from triglyceride-rich lipoproteins for use in cellular metabolic reactions. How this hydrolysis, which occurs at the vascular endothelium, is regulated is poorly understood. A fatty acid feedback system has been proposed by which accumulation of fatty acids impedes LPL-catalyzed hydrolysis and dissociates the enzyme from its endothelial binding sites. We examined this hypothesis in humans who were subjected to an oral fat tolerance test of a mixed-meal type. Plasma triglycerides, free fatty acids, and LPL activity were measured before and repeatedly during a 12-h period after intake of the fat load. Since soybean oil with a high content of linoleic fatty acid was the source of triglycerides, a distinction could be made between endogenous free fatty acids (FFA) and FFA derived directly from lipolysis of postprandial triglyceride-rich lipoproteins. Mean LPL activity was almost doubled (P less than 0.01) 6 h after intake of the oral fat load. The rise in LPL activity was accompanied by an increase of plasma triglycerides and linoleic free fatty acids (18:2 FFA), but not of total plasma FFA, which instead displayed a heterogeneous pattern with essentially unchanged mean levels. The postprandial response of LPL activity largely paralleled the postprandial responses of 18:2 FFA and triglycerides. The highest degree of parallelism was seen between postprandial 18:2 FFA and LPL activity levels. Furthermore, the integrated response (area under the curve, AUC) for plasma measurements of LPL correlated with the AUC for 18:2 FFA (r = 0.40, P less than 0.05), but not with the AUC for plasma triglycerides (r = 0.21, ns). The high degree of parallelism and significant correlation between postprandial plasma LPL activity and 18:2 FFA support the hypothesis of fatty acid control of endothelial LPL during physiological conditions in humans.

Dietary Fats↗
PubMed2000

Relationship of abdominal adiposity and dyslipemic status in women with a common mutation in the lipoprotein lipase gene. The REGICOR investigators.

Abdominal obesity constitutes an important risk factor for cardiovascular disease. Hypertriglyceridemia and low high-density lipoprotein (HDL) cholesterol concentration constitute the major lipid alterations observed in obesity. A common variant of the lipoprotein lipase (LPL) gene, the HindIII polymorphism, has been found to be associated with changes in triglyceride and HDL-cholesterol levels. We have investigated the impact of the LPL HindIII polymorphism on the relationship between abdominal adiposity and lipoprotein concentrations in 156 randomly selected women in a cross-sectional study conducted in the province of Gerona, in the northeast of Spain. The waist-to-hip ratio was used as an estimate of regional fat distribution. Serum lipid and lipoprotein measurements as well as lipoprotein lipase-HindIII genotypes were determined. Percentile 50 of waist-to-hip ratio (WHR) (0.81) was used as a cutoff to define low or high WHR groups, which significantly differed in blood pressure and lipid trait concentrations. Serum triglyceride concentrations and mean log triglyceride-to-HDL-cholesterol ratio were significantly higher in H+ homozygous women compared with H- carriers. Whereas no statistically-significant differences were observed in HDL-cholesterol concentration and log triglyceride-to-HDL-cholesterol ratio of H- carriers between WHR groups, H+ homozygous women showed significant differences in these lipid traits. It is noteworthy that high-WHR H- carrier women showed a mean HDL-cholesterol value similar to those of both genotypes in the low WHR group. A statistically significant interaction between WHR and genotype was observed for HDL-cholesterol concentration (P=0. 027) and log triglyceride-to-HDL-cholesterol ratio (P=0.040). These results stress the compensating effects that weight loss may have on women with adverse genetic factors. From a complementary viewpoint, the presence of the H- allele seems to confer a protective lipid profile, even when an adverse anthropometric factor such as abdominal adiposity is present.

Abdomen↗
PubMed1984

Irradiation-induced free cholesterol accumulation in very-low-density lipoproteins. Role of lipoprotein lipase deficiency.

Irradiation of rabbits induced an accumulation of free cholesterol in VLDL fraction. In the present study, an attempt was made to explain the abnormal free cholesterol enhancement. The study demonstrated that lecithin:cholesterol acyltransferase activity was normal in irradiated rabbits. In addition, electron microscopy examination of HDL revealed no changes after irradiation: spherical particles were present. On the other hand, ACAT activity was increased while neutral and acidic cholesteryl esterases were strongly decreased. Moreover, HMG-CoA reductase was 3-fold reduced after irradiation. These results show that neither cholesterol esterification nor cholesterol ester hydrolysis nor cholesterol biosynthesis are responsible for this increase of free cholesterol in VLDL. In contrast, we have shown that extra-hepatic lipoprotein lipase was deficient in irradiated rabbit plasma although synthesis in the adipocytes is normal. To investigate a hypothetical deficiency of VLDL catabolism, we performed experiments with injection of heparin and with labeled VLDL. These experiments show that, in irradiated rabbits, VLDL were not catabolized, since the radioactivity was recovered only in the VLDL fraction. This impaired VLDL removal was compatible with the deficiency of extra-hepatic lipoprotein lipase activity.

Adipose Tissue↗