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PubMed1990

Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages.

Lipoprotein lipase (LPL) (EC 3.1.1.34) hydrolyzes triacylglycerols of very low density lipoproteins and chylomicrons. It is produced by several cell types, including macrophages, which are frequent in atherosclerotic lesions. The atherosclerotic plaque also contains activated T lymphocytes. We therefore investigated the possible regulatory effect of the T lymphocyte-derived lymphokine interferon-gamma (IFN-gamma) on macrophage LPL. Human monocyte-derived macrophages were treated with recombinant IFN-gamma or conditioned medium from activated peripheral blood mononuclear cells for 3 days. LPL activity was thereafter measured in the culture medium and in cell homogenates. The enzyme protein was detected at a cellular level by immunocytochemistry and immunopredicipitation. Recombinant IFN-gamma caused a profound decrease in macrophage LPL secretion. The IFN-gamma-treated cells, however, still contained immunodetectable enzyme and the decrease in secretion was apparently only partly due to an inhibited synthesis. Conditioned medium from activated peripheral blood mononuclear cells also drastically decreased the macrophage LPL secretion. When the conditioned medium was treated with antibodies against IFN-gamma, its down-regulating effect on macrophage LPL was totally removed. The data indicate that IFN-gamma is inhibiting macrophage LPL at least in part via a reduction of LPL synthesis. A local release of IFN-gamma may be important in the pathogenesis of atherosclerosis by affecting the lipid accumulation in the lesion.

Cells, Cultured↗
PubMed1991

Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions.

Lipoprotein lipase (LPL; EC 3.1.1.34) may promote atherogenesis by producing remnant lipoproteins on the endothelial surface and by acting on lipoproteins in the artery wall. In vitro, smooth muscle cells and macrophages synthesize LPL, but in human carotid lesions only a few smooth muscle cells were reported to contain LPL protein. Endothelial cells do not synthesize LPL in vitro, but in normal arteries intense immunostaining for LPL is present on the endothelium. We used Northern blot analysis, in situ hybridization, and immunocytochemistry of human and rabbit arteries to determine cellular distribution and the site of the synthesis of LPL in atherosclerotic lesions. Northern blot analysis showed that LPL mRNA was detectable in macrophage-derived foam cells isolated from arterial lesions of "ballooned" cholesterol-fed rabbits. In situ hybridization studies of atherosclerotic lesions with an antisense riboprobe showed a strong hybridization signal for LPL mRNA in some, but not all, lesion macrophages, which were mostly located in the subendothelial and edge areas of the lesions. Also, some smooth muscle cells in lesion areas also expressed LPL mRNA. Immunocytochemistry of frozen sections of rabbit lesions with a monoclonal antibody to human milk LPL showed intense staining for LPL protein in macrophage-rich intimal lesions. The results suggest that lesion macrophages and macrophage-derived foam cells express LPL mRNA and protein. Some smooth muscle cells in the lesion areas also synthesize LPL. These data are consistent with an important role for LPL in atherogenesis.

Animals↗
PubMed1999

Newly identified missense mutation reduces lipoprotein lipase activity in Taiwanese patients with hypertriglyceridemia.

Lipoprotein lipase (LPL) plays a crucial role in the regulation of lipoprotein metabolism by hydrolyzing the core triglycerides of circulating chylomicrons and very low-density lipoprotein. Deficiency in this enzyme usually results in disturbances in lipid levels. To understand the molecular defect that leads to a functional deficiency of LPL in patients with hypertriglyceridemia, we looked for mutations of the LPL gene by means of single-strand conformation polymorphism (SSCP) analysis and direct DNA sequencing in 24 patients. A single base C-->G substitution in codon 252 of the LPL gene, encoding a change of a leucine to a valine residue in the mature protein, was found in three women who had hypertriglyceridemia and recurrent pancreatitis. Two of these patients, who were homozygous for the L252V mutation, had variable and occasionally severe hypertriglyceridemia with undetectable or very low LPL activities, respectively. The third woman was heterozygous for this mutation. All three patients had poor post-heparin LPL activity. Site-directed mutagenesis experiments provided in vitro evidence that the mutation of codon 252 was responsible for the loss of LPL activity. In conclusion, we identified a novel LPL mutation that results in decreased LPL activity in Taiwanese patients with hypertriglyceridemia. The assessment of a causative link between the mutation and hyperlipidemia awaits further studies.

Adult↗
PubMed1984

An enzymatic assay for activity of lipoprotein lipase.

An enzymatic method for the determination of the amount of free fatty acids released from triglyceride by lipoprotein lipase is described. The quantity of free fatty acids present in media before and after incubation is measured spectrophotometrically by the oxidation of NADH in the final reaction of a series of coupled enzymatic reactions. This assay for lipoprotein lipase is unlike previously described assays in that radioactive substrates or titration procedures are not used in the free fatty acid determination. In addition, another method for assay of lipoprotein lipase activity that involves the separation of free fatty acids from triglycerides by adsorption chromatography with Florisil as a stationary phase is described.

Adipose Tissue↗
PubMed1980

Lipoprotein lipase activity of rat cardiac muscle. Changes in the enzyme activity during incubations of isolated cardiac-muscle cells in vitro.

1. Isolated cardiac-muscle cells from the hearts of adult rats were shown to retain a high amount of viability during 4 h of incubation when viability was assessed by Trypan Bue stain exclusion and intracellular enzyme leakage. 2. The cells also retained their ability to take up O2 and utilize added substrates over the period of incubation at both 25 and 30 degrees C. 3. When cells from the hearts of fed rats were incubated in a buffered-salts solution at pH 7.4 in the presence of amino acids and heparin, lipoprotein lipase activity in the medium increased progressively. 4. During these incubations the intracellular activity of the enzyme remained constant and the total activity of lipoprotein lipase in the system (cells plus medium) increased by 80% over the 4 h of incubation at 25 degrees C. 5. In the absence of heparin only low amounts of enzyme activity were detectable in the medium and the total lipoprotein lipase activity in the system remained constant. 6. The measurement of lipoprotein lipase activity in either fresh homogenates of the cells or in homogenates of acetone/diethyl ether-dried powders of the cells had no effect on the overall pattern of activity change during the incubations, although as reported previously the total activity detected with acetone/diethyl either-dried preparations was approx. 3-fold higher than with fresh cell homogenates. 7. The observations were compared with published data on lipoprotein lipase activity changes in neonatal heart cell cultures maintained in vitro.

Animals↗
PubMed1979

Effect of high carbohydrate feeding with dextrose or sucrose on adipose tissue lipoprotein lipase activity and plasma triglyceride levels in hemodialysis patients.

The acute effect of feeding high concentration carbohydrate meals containing equicaloric amounts of dextrose or sucrose on the activity of adipose tissue lipoprotein lipase and the concentration of plasma triglyceride was assessed in 11 hemodialysis patients. Dextrose feeding resulted in higher postprandial glucose levels and a greater insulin response than sucrose. The relationship between the postprandial change in the activity of adipose tissue lipoprotein lipase and the insulin response to feeding almost reached statistical significant (rs = 0.40, P = 0.08, n = 20), and the increase in the activity of the enzyme after dextrose feeding was greater than after sucrose (P less than 0.01). There was a significant decrease in plasma triglyceride levels after dextrose feeding (P less than 0.01), but no change was observed after the ingestion of sucrose. These results indicate that the inability of the administered sucrose to raise the plasma insulin concentration to the same level as isocaloric amounts of dextrose probably accounts for the smaller increase in the activity of adipose tissue lipoprotein lipase after sucrose. The failure of plasma triglyceride levels to fall after sucrose feeding suggests that the extent to which the activity of adipose tissue lipoprotein lipase increases postprandially may be important in the regulation of triglyceride metabolism in hemodialysis patients.

Adipose Tissue↗
PubMed1980

The validation and use of specific methods for the estimation of lipoprotein lipase and hepatic lipase activities in post-heparin plasma of children with hyperlipidaemia.

The methods proposed by Nilsson-Ehle and Ekman [8] for the specific estimation of lipoprotein lipase and hepatic lipase activities in post-heparin plasma were investigated. The procedure for hepatic lipase was found to be specific, but the lipoprotein lipase assay required modification to abolish hepatic lipase interference. The modified procedures were fully validated and found to be relatively simple, rapid and specific and were used to investigate children with primary and secondary hyperlipidaemic states.

Adolescent↗
PubMed1993

Effects of probucol and pravastatin on plasma lipids, activities of postheparin lipoprotein lipase, and lecithin cholesterol acyltransferase and apo A-I containing lipoproteins with and without apo A-II in patients with moderate hypercholesterolemia.

In this study, plasma HDL fractions were separated by ultracentrifugation and apo A-I containing lipoproteins (A-I Lp) were then isolated using anti-apo A-I immunoaffinity chromatography. The A-I Lp were further separated into two fractions with the use of anti-apo A-II immunoaffinity chromatography. One fraction, Lp A-I, contained apo A-I without apo A-II, while the other, Lp A-I/A-II, contained both apo A-I and apo A-II. These techniques were applied to investigate the changes in HDL apoprotein composition in hypercholesterolemic subjects treated with either probucol or pravastatin. Treatment with probucol (500 mg/day) or pravastatin (10 mg/day) reduced mean plasma total cholesterol concentrations by 24% (p < 0.01) and 16% (p < 0.05), respectively. Both drugs caused some reduction in lipoprotein lipase activity, but neither had any influence on the activity of hepatic triglyceride lipase or lecithin cholesterol acyltransferase. Their effects on HDL-cholesterol levels and apoprotein composition differed markedly. Probucol significantly decreased the HDL-cholesterol concentration, the plasma apo A-I/apo A-II ratio, and the number of large particles of diameter greater than 10.4 nm. When the ratios of Lp A-I and Lp A-I/A-II for the probucol-treated subjects were compared with those in the normolipidemic controls, and with the ratios before and after administration of probucol, a remarkable decrease in the level of Lp A-I was apparent. It is presumed that the decrease in HLD-cholesterol by prolonged probucol administration reflects the decrease of Lp A-I more than the decrease of Lp A-I/A-II.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein A-I↗
PubMed1986

Hypercholesterolaemia, hypotriacylglycerolaemia and increased lipoprotein lipase activity following orchidectomy in rats.

Plasma lipoproteins, faecal cholesterol excretion, and activities of lecithin: cholesterol acyltransferase (LCAT) hepatic lipase (HL), and lipoprotein lipase (LPL) were determined in castrated rats, in rats treated with testosterone propionate after castration, and in sham-operated controls. Compared to control rats, whole-plasma total cholesterol (TC) rose, and triacylglycerols (TG) fell in castrated rats, but were normalized by androgen substitution. VLDL components tended to be reduced, whereas HDL2 components rose following castration. In general, testosterone substitution normalized the alterations induced by castration. Adipose tissue LPL was higher in castrated rats than in control rats, whereas activities of HL and LCAT were not significantly affected by the treatments. Hepatic cholesterol concentration, and faecal excretion of cholesterol and bile acids were not significantly altered by the treatments. Considering all 3 groups together, there was a significant positive correlation between the concentration of plasma cholesterol and cholesterol in liver, between plasma HDL2-cholesteryl esters and hepatic cholesterol, and also between HL and faecal cholesterol excretion. The results suggest that short term castration of rats causes increased levels of lipoprotein lipase and thereby brings about a lowering of VLDL and an increased concentration of LDL and HDL2. These effects are reflected in hypotriacylglycerolaemia and hypercholesterolaemia.

Animals↗
PubMed1978

The lipoprotein lipase system: new understandings.

Hypertriglyceridemia, a risk factor for premature atherosclerosis, may result from decreased use of plasma triglycerides by tissues. The removal of triglycerides is mediated by the enzyme lipoprotein lipase (LPL). Heparin releases LPL from tissues and post-heparin plasma lipolytic activity (PHLA) has been extensively used to elucidate the mechanism of hypertriglyceridemia in various diseases. There is evidence to show that postheparin plasma contains enzymes other than LPL. Hence data on total PHLA are difficult to interpret. Availability of assays for the LPL component of PHLA has clarified equivocal findings in certain hypertriglyceridemic states. However, the LPL component is also heterogeneous. The LPL "isoenzymes" from various extrahepatic tissues behave differently under various metabolic conditions. Therefore, to understand properly the LPL system it is necessary to study the specific tissue LPL. Furthermore, the serum activator for LPL is now characterized. Its importance is evidenced by the recent discovery of a hypertriglyceridemic patient deficient in this apoprotein.

Adipose Tissue↗
PubMed1990

Lipoprotein lipase prevents the hepatic lipase-induced reduction in particle size of high density lipoproteins during incubation of human plasma.

Human plasma lipoproteins or human whole plasma have been incubated in vitro with canine hepatic lipase (HL) and bovine milk lipoprotein lipase (LPL) to determine the effects of lipases on the particle size distribution of HDL. Confirming previous reports, HL preferentially hydrolysed high density lipoprotein (HDL) triacylglycerol while LPL hydrolysed predominantly very low density lipoprotein (VLDL) triacylglycerol; however, neither lipase altered HDL particle size unless both VLDL and cholesteryl ester transfer protein (CETP) were present. Under these conditions HL promoted marked reduction in HDL particle size in a process dependent on the concentration of VLDL triacylglycerol while LPL was virtually without effect. When both LPL and HL were included in the same incubation, however, LPL prevented the effects of HL. These results are consistent with a proposition that HL has a direct effect on HDL particle size in a process which is dependent on concurrent lipid transfers between HDL and VLDL and that LPL reduces the effect of HL by reducing the concentration of VLDL triacylglycerol.

Carrier Proteins↗
PubMed1986

High-density lipoprotein cholesterol, hepatic lipase and lipoprotein lipase activities in thyroid dysfunction--effects of treatment.

We have investigated the effects of hyper- and hypothyroidism (clinical and subclinical) on lipid metabolism, with special emphasis on serum high-density lipoprotein cholesterol, post-heparin plasma hepatic lipase and lipoprotein lipase activities. In 16 patients with hyperthyroidism, increased post-heparin plasma hepatic lipase activity, decreased serum total cholesterol and serum high-density lipoprotein cholesterol were found while lipoprotein lipase activity and serum triglyceride were normal. In six patients with overt hypothyroidism serum total cholesterol and triglyceride were increased, post-heparin plasma hepatic lipase and lipoprotein lipase were decreased while serum high-density lipoprotein cholesterol was normal. In six patients with subclinical hypothyroidism, serum total cholesterol was increased, serum high-density lipoprotein cholesterol was decreased, while serum triglyceride, post-heparin plasma hepatic lipase and lipoprotein lipase were normal. When the three groups of patients became euthyroid, serum total cholesterol, serum triglyceride, post-heparin plasma hepatic lipase, lipoprotein lipase, and serum high-density lipoprotein cholesterol reverted to normal except for serum high-density lipoprotein cholesterol in the hyperthyroid group which showed no significant change with treatment. A positive correlation was found between serum T3 and post-heparin plasma hepatic lipase while negative correlations were found between serum total cholesterol and serum T3, post-heparin plasma hepatic lipase and serum total cholesterol, lipoprotein lipase and serum triglyceride respectively. Thus in these patients with thyroid dysfunction, significant reversible alterations in serum total cholesterol, triglyceride and high-density lipoprotein cholesterol were found and could be correlated with the observed changes in the activities of hepatic lipase and lipoprotein lipase.

Adult↗
PubMed1982

Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells.

Conditioned medium from cultures of mouse peritoneal exudate cells incubated wih endotoxin contains a mediator that markedly suppresses (greater than 90%) lipoprotein lipase (triacylglycero-protein acylhydrolase, EC 3.1.1.34) activity in differentiating 3T3-L1 mouse preadipocytes. The effect is dependent upon the amount of mediator and is evident as early as 30 min after the addition of the mediator-containing medium to 3T3-L1 cell cultures. Neither endotoxin nor conditioned medium from cultures of exudate cells not exposed to endotoxin shows the presence of the mediator. Lysates of the exudate cells are also unable to suppress the lipase activity. Increasing the amount of insulin does not reverse this suppression, even at 1000 times the concentration used for standard experiments. The lipoprotein lipase suppression mediator present in the conditioned medium of endotoxin-treated exudate cells is heat labile and has an apparent molecular weight of at least 12,000. The mediator does not inhibit lipoprotein lipase activity directly nor does it affect the half-life of enzyme activity released in the medium. The present study demonstrates that endotoxin promotes the release of a mediator from exudate cells that suppresses the activity of lipoprotein lipase in 3T3-L1 preadipocytes.

Adipose Tissue↗
PubMed1995

Postprandial lipid and hormone responses to meals of varying fat contents: modulatory role of lipoprotein lipase?

OBJECTIVE: Substrate and hormone responses to meals of differing fat content were evaluated in normal subjects in order to investigate mechanisms underlying the regulation of postprandial lipoprotein concentration. DESIGN: A randomised cross-over study with three different meals on three occasions. SETTING: Free-living subjects associated with Surrey University. SUBJECTS: Ten male volunteers (aged 18-23 years) were recruited. INTERVENTIONS: Three test meals containing 20, 40 or 80 g fat but identical carbohydrate and protein content were randomly allocated to volunteers. MAJOR OUTCOME MEASURES: Pre- and postprandial blood samples were taken for the analysis of plasma triacylglycerol, non-esterified fatty acids, glucose, immunoreactive insulin and glucose-dependent insulinotrophic polypeptide levels and postheparin lipoprotein lipase activity measurements. RESULTS: Peak triacylglycerol concentrations and lipoprotein lipase activity measurements were significantly higher following the 80 g than the 20 g fat meal (P = 0.009 and P = 0.049 respectively). Areas under the glucose-dependent insulinotrophic polypeptide time-response concentration curves were significantly higher following the 80 g compared with the 20 g fat meal (P = 0.04), but no differences in insulin response to the meals were seen. The 30-360 min decrease in the non-esterified fatty acid concentration was less following the 80 g than the 20 g meal (P = 0.001). CONCLUSIONS: The results suggest that glucose-dependent insulinotrophic polypeptide may mediate increased lipoprotein lipase activity in response to fat-containing meals and may play a role in circulating lipoprotein homeostasis. This mechanism may be overloaded with high fat meals with adverse consequences on circulating triacylglycerol and NEFA concentrations.

Adolescent↗
PubMed1993

High-density lipoprotein cholesterol concentrations and postheparin hepatic and lipoprotein lipases in obesity: relationships with plasma insulin levels.

The concentration of high-density lipoprotein (HDL) cholesterol in patients with severe obesity is generally subnormal. The exact mechanism linking obesity with reduced levels of HDL cholesterol remains unclear. In this study we evaluated the postheparin plasma lipolytic enzymes lipoprotein lipoprotein lipase (LPL) and hepatic lipase (HL) in a group of 24 obese women compared with controls and analyzed the interrelationships between insulin, postheparin lipolytic enzymes and HDL subfractions. Total HDL cholesterol was significantly lower in the obese subjects than in the controls, and the difference was mainly due to HDL2 cholesterol concentrations. Mean fasting glucose, insulin and the summated means of glucose (sigma glucose) after the oral glucose tolerance test (OGTT) were not significantly different in the two groups. The summated means of insulin (sigma IRI) after the OGTT were significantly higher in the obese women than in the controls. LPL, HL and the HL-to-LPL ratio were significantly higher in the obese women than in the controls. HL and LPL correlated positively with sigma glucose, sigma IRI and body mass index (BMI) and negatively with plasma triglycerides. Partial correlation analysis demonstrated that, when exposed to similar sigma IRI values, HL and LPL were no longer correlated with sigma glucose, plasma triglycerides and BMI. HDL2 cholesterol levels were negatively correlated with HL, posthepatic plasma lipolytic activity, sigma glucose, plasma triglycerides and BMI. HDL2 cholesterol concentrations were directly correlated with LPL. Partial correlation analysis showed that when exposed to similar HL and LPL values, HDL2 cholesterol values were no longer correlated with sigma glucose, sigma IRI, plasma triglycerides and BMI. Therefore, our results demonstrate that the low HDL2 cholesterol levels found in obese women may be related to the high levels of HL and to the high HL-to-LPL ratio which in turn could be determined by the peripheral insulin resistance.

Adult↗
PubMed1988

Insulin-stimulated release of lipoprotein lipase by metabolism of its phosphatidylinositol anchor.

Lipoprotein lipase (LPL) plays a critical role in the metabolism of plasma lipoproteins. In 3T3-L1 adipocytes, insulin elicits the rapid release of LPL through mechanisms that are independent of energy metabolism and protein synthesis. Some of the metabolic actions of insulin may be mediated by the activation of a specific phospholipase that hydrolyzes a glycosyl phosphatidylinositol (PI) molecule. The insulin-sensitive glycosyl-PI is structurally similar to the glycolipid membrane anchor of a number of proteins. LPL appears to be anchored to the 3T3-L1 cell surface by glycosyl-PI, and its rapid release by insulin may be due to activation of a glycosyl-PI-specific phospholipase C.

Adipose Tissue↗
PubMed1984

Lipoprotein lipase enhances the cholesteryl ester transfer protein-mediated transfer of cholesteryl esters from high density lipoproteins to very low density lipoproteins.

These studies were undertaken to examine the effects of lipoprotein lipase (LPL) and cholesteryl ester transfer protein (CETP) on the transfer of cholesteryl esters from high density lipoproteins (HDL) to very low density lipoproteins (VLDL). Human or rat VLDL was incubated with human HDL in the presence of either partially purified CETP, bovine milk LPL or CETP plus LPL. CETP stimulated both isotopic and mass transfer of cholesteryl esters from HDL into VLDL. LPL caused only slight stimulation of cholesteryl ester transfer. However, when CETP and LPL were both present, the transfer of cholesteryl esters from HDL into VLDL remnants was enhanced 2- to 8-fold, compared to the effects of CETP alone. The synergistic effects of CETP and LPL on cholesteryl ester transfer were more pronounced at higher VLDL/HDL ratios and increased with increasing amounts of CETP. In time course studies the stimulation of cholesteryl ester transfer activity occurred during active triglyceride hydrolysis. When lipolysis was inhibited by incubating LPL with either 1 M NaCl or 2 mM diethylparanitrophenyl phosphate, the synergism of CETP and LPL was reduced or abolished, and LPL alone did not stimulate cholesteryl ester transfer. These experiments show that LPL enhances the CETP-mediated transfer of cholesteryl esters from HDL to VLDL. This property of LPL is related to lipolysis.

Carrier Proteins↗