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T Olivecrona

Publications and source records attributed to T Olivecrona.

At least 37 records · Page 2Linked to original sources
PubMed1996

Forms of lipoprotein lipase in rat tissues: in adipose tissue the proportion of inactive lipase increases on fasting.

Previous studies have shown that the ratio of lipoprotein lipase (LPL) catalytic activity to LPL mass in tissues differs in different conditions, but it is not clear whether this occurs by a change in the catalytic efficiency of the LPL molecules, or because of a shift in the relation between active and inactive forms of the enzyme. To explore this, we have measured LPL activity and mass in detergent extracts of rat tissues. LPL specific activity was high and similar in heart, skeletal muscle, lung and brain. The liver had significantly lower specific activity, which is in accord with previous findings that the liver takes up and catabolizes LPL. The specific activity was also low in adipose tissue from fasted rats. When tissue extracts were applied to columns of heparin-agarose and eluted by a gradient of NaCl, a peak of active LPL was eluted at 1.0 M NaCl, but there was also a peak of inactive LPL protein, which was eluted at 0.6 M NaCl. In adipose tissue, LPL activity decreased by 70-80% during an overnight fast, whereas LPL mass decreased by only 20-40%. The mass ratio between inactive and active LPL, as separated by heparin-agarose chromatography, increased from 0.5 to over 2 during the fast. In hearts there was no significant difference between fed and fasted rats in total LPL activity, LPL mass or in the distribution between inactive and active forms. The results indicate that the relation between inactive (probably monomeric) and active (dimeric) forms of LPL is a target for post-translational regulation in adipose tissue.

Adipose Tissue↗
PubMed1996

High-density lipoprotein: relations to metabolic parameters and severity of coronary artery disease.

The regulation of plasma high-density lipoprotein (HDL) cholesterol level by the joint influence of plasma lipoprotein lipids, lipoprotein lipase (LPL), hepatic lipase (HL), cholesteryl ester transfer protein (CETP), oral glucose tolerance, and postload plasma insulin and proinsulin levels was investigated in young postinfarction patients and healthy population-based control subjects. In addition, the association between HDL cholesterol and the number and severity of coronary stenoses previously reported in this cohort of young postinfarction patients was further investigated by analyzing the determinants and angiographic relations of HDL subclasses measured by gradient gel electrophoresis. The following parameters showed significant univariate relations with HDL cholesterol level in the patient group: very-low-density lipoprotein (VLDL) cholesterol and triglyceride, low-density lipoprotein (LDL) triglyceride, and postload plasma insulin concentrations, preheparin plasma LPL mass, and postheparin plasma HL activity. In the control group, significant correlations with HDL cholesterol concentration in addition to those noted among the patients were found for body mass index (BMI), LDL cholesterol level, postload plasma intact proinsulin concentration, and LPL activity in postheparin plasma. In contrast to the patients, no significant relations were noted for postload plasma insulin level and preheparin plasma LPL mass. Multiple stepwise regression analysis showed that 42% of the variability of HDL cholesterol in the patients could be accounted for by VLDL cholesterol concentration (29%), LDL triglyceride level (7%), and postheparin plasma HL activity (8%), whereas the corresponding figure in controls was 35% (VLDL cholesterol concentration [9%] and postheparin plasma HL activity [26%]. The strength of the relationships of HDL cholesterol and HDL subclasses to the coronary stenosis score was similar and statistically significant (r = .25 to .36). When the metabolic parameters that correlated with HDL cholesterol and HDL subclass concentrations in univariate analysis were used as covariates, all relations to the coronary stenosis score disappeared. This clearly indicates that the influence of triglyceride-rich lipoproteins and lipolytic enzymes needs to be considered when assessing the association between HDL cholesterol and coronary artery disease (CAD).

Adult↗
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↗
PubMed1996

Synthesis and secretion of lipoprotein lipase in heparan sulfate-deficient Chinese hamster ovary cells.

Synthesis and secretion of lipoprotein lipase was studied in two mutants of Chinese hamster ovary (CHO) cells which, due to a lack of xylosyl transferase (pgsA-745) or galactosyl transferase (pgsB-761), respectively, were deficient in heparan sulfate and chondroitin sulfate. One of the mutants (pgsB-761) was two- to threefold more active in synthesis and secretion of catalytically active lipoprotein lipase than the other mutant, which was about as active as the wild-type (K1) cells. A similar relation was found when lipoprotein lipase was metabolically labelled with 35S-methionine and then immunoprecipitated. Heparin stimulated secretion from all three cell types to a similar extent (about twofold). Heparin-releasable binding of 125I-labelled lipoprotein lipase was lower to either of the mutant cells than to the wild-type cells. Binding to the wild-type cells was reduced by heparitinase, while the low binding to the mutants was not affected. By immunogold labelling of cryosections, lipoprotein lipase was detected on the plasma membranes and on the inside of secretory vesicles of both wild-type and mutant cells, suggesting that some carrier could be involved. Inhibition of vesicular transport by monensin caused accumulation of lipoprotein lipase in the cells. In wild-type cells the lipase was mainly on the inside of vesicular structures, while in the mutants the main part was associated with membranous bodies that formed within the vesicles during a chase period. These results suggest that if lipoprotein lipase needs a carrier during intracellular assembly and transport, this function can be fulfilled by some structure other than heparan sulfate.

Animals↗
PubMed1996

Heparan sulfate-dependent and low density lipoprotein receptor-related protein-dependent catabolic pathways for lipoprotein lipase in mouse embryonic fibroblasts.

Heparan sulfate and low density lipoprotein receptor related protein (LRP) have been shown to participate in the uptake and degradation of the enzyme lipoprotein lipase (LPL). Yet, the contribution of each of these pathways to LPL metabolism and their possible dependence is unknown. In the present study we examined the metabolism of 125I-labeled LPL in untreated and heparinase-treated primary wild-type mouse embryonic fibroblasts (MEF) and in mouse fibroblasts that express single LRP allele (PEA-10) or are lacking the LRP (PEA-13). The degradation of LPL in PEA-13 cells was 30% lower than in MEF and PEA-10 cells. Heparinase treatment decreased the LPL degradation by 58%, 79% and 92%, whereas heparin reduced such degradation by 87%, 90% and 94% in MEF, PEA-10 and PEA-13 cultures, respectively. Assuming that a) heparinase treatment abolished the heparan-sulfate pathway, and that b) the degradation remaining in heparin-treated cultures represents nonspecific values, it appears that heparan sulfate contributes about 61%, 83% and 95% of total LPL degradation, whereas the LRP pathway contributes 39%, 17% and less than 5% of LPL degradation in MEF, PEA-10 and PEA-13 cells, respectively. In addition, the data indicate that LPL interaction with heparan sulfate and the LRP pathways is independent of each other. The study shows that these cells possess both a heparan sulfate-dependent pathway and an LRP-dependent pathway for LPL metabolism and that the two pathways are independent of each other.

Alleles↗
PubMed1996

Chylomicron metabolism in rats: lipolysis, recirculation of triglyceride-derived fatty acids in plasma FFA, and fate of core lipids as analyzed by compartmental modelling.

Chylomicrons labeled in vivo with [14C]oleic acid (primarily in triglycerides (TG), providing a tracer for lipolysis) and [3H]retinol (primarily in ester form, providing a tracer for the corelipids) were injected into rats. Disappearance of the two labels from plasma and appearance of label in plasma free fatty acids (FFA) were analyzed by compartmental modelling. Both core and TG label distributed into an apparent volume 10-15% larger than the blood volume. Part of this probably represents margination to endothelial-binding-lipolysis sites. An open two-compartmental model for plasma FFA was derived from experiments where unesterified oleic acid complexed to albumin was injected. Applying this model revealed that most of the oleic acid from chylomicron triglycerides mixes with the FFA. The disappearance of chylomicron core label required a model in which the label transfers into a second compartment before it leaves the blood. The rate constant for the transformation was high and predicted that, on average, chylomicron spent less than 2 min in the first compartment. The rate out from the second compartment predicted that about 60% of the core label left blood while, on average, chylomicron retained more than half of its triglyceride molecules, i.e., after rather limited lipolysis. The mechanism by which the core label leaves blood is not clear. Modelling showed that under the assumption that the process is shared by chylomicron triglycerides, about half of them go out by this pathway. Comparing fed and fasted rats, the main differences were in the turnover of FFA and in the extent to which chylomicron TG label reappeared in the FFA. This study indicates that a large fraction of the triglycerides in chylomicrons leave plasma together with the core lipids and that most of the fatty acids from chylomicron triglycerides mix into the same metabolic compartments as do plasma free fatty acids.

Animals↗
PubMed1995

Binding to heparan sulfate is a major event during catabolism of lipoprotein lipase by HepG2 and other cell cultures.

Lipoprotein lipase (LPL) is rapidly and efficiently cleared from the circulation by the liver through an as yet unclear mechanism. In the present study, we determined the nature of LPL interactions with the liver parenchimal cell line HepG2 as compared to other cells in culture. Binding, cell association and degradation of 125I-labelled bovine milk LPL by HepG2 cells, normal and low density lipoprotein (LDL) receptor-negative human fibroblasts and Chinese hamster ovary (CHO) cells show similar values irrespective of source and origin. LPL metabolism in HepG2 cells was characterized by a high capacity to degrade the enzyme, an extremely high sensitivity to heparin and was inhibited by 60%-70% after treatment of the cells with sodium chlorate and heparinase (but not chondroitinase). These findings suggested an important role for heparan sulfate in the process of cell interaction and metabolism of LPL. To further clarify the role of heparan sulfate in determining the LPL-cell interactions, we compared the metabolism of LPL in wild type and mutant heparan sulfate-deficient CHO cells. Heparan sulfate-deficient CHO cells show a low capacity to bind and degrade LPL, about 10%-20% that of the wild type cells. In another set of experiments, we sought to determine whether LPL interactions with HepG2 cells are affected by triglyceride-rich lipoproteins. The results clearly show that whereas unlabeled LPL dramatically enhanced the metabolism of radioiodinated very low density lipoprotein (VLDL), unlabeled VLDL had no effect on radioiodinated LPL metabolism in these cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Triglyceride lipases and atherosclerosis.

Lipoprotein lipase is at the center of lipoprotein metabolism, unloading triglycerides for metabolic use in extrahepatic tissues, regulated in concert with energy metabolism by insulin and other factors, and converting the input of large triglyceride-rich lipoproteins to smaller, potentially atherogenic remnants that are either remodeled into LDL and HDL, or quickly cleared. In addition, lipoprotein lipase has turned out to be a multifunctional protein that also acts as a ligand for binding of lipoproteins to proteoglycans and receptors. Hepatic lipase has evolved more recently, and its main role appears to be in the remodeling processes.

Arteriosclerosis↗
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↗
PubMed1995

Nutritional regulation of lipoprotein lipase.

Lipoprotein lipase (LPL) is needed for normal catabolism of triglyceride-rich lipoproteins. In some tissues, notably the adipose tissue, the local LPL activity is an important determinant for how much lipid is taken up. There is regulation of gene expression, but the rapid changes that occur in response to the nutritional state are mediated mainly by post-transcriptional mechanisms. In the fed state, the adipose tissue expresses its full potential for LPL production, as set by the mRNA levels and the rate of protein synthesis. During fasting, LPL activity is suppressed by an unknown post-translational mechanism. In heart, regulation is primarily exerted on the equilibrium between LPL at endothelial sites and LPL in blood, with more endothelial LPL in the fasted state. LPL forms complexes with fatty acids which results in shut-down of lipolysis and detachment of both lipase and lipoproteins from the endothelial site. This provides a molecular coupling device between the cellular metabolic state and the rate of lipoprotein catabolism. There is growing evidence that LPL is a ligand for binding of lipoprotein particles such as chylomicron remnants to cell surfaces and receptors.

Adipose Tissue↗
PubMed1995

[The great Scandinavian Medical Jahre Prize 1994. Role of lipoprotein lipase in lipoprotein metabolism].

Each day more than 150 g of triglycerides are transported from the intestine in chylomicrons and from the liver in VLDL. The triglycerides are hydrolyzed by lipoprotein lipase at the vascular endothelium in extrahepatic tissues. This releases fatty acids and monoglycerides which can move across aqueous barriers and cell membranes to reach metabolic sites in tissue cells. At the endothelial cell the enzyme is anchored to heparin sulfate proteoglycans. The enzyme is located in a position where it can freely interact with lipoproteins from the circulating blood. The hydrolysis is a rapid and efficient process. A chylomicron containing more than a million triglyceride molecules can be unloaded in less than 10 minutes. As a consequence of triglyceride hydrolysis the lipoproteins are reduced to remnant particles. Some of these are rapidly removed from plasma but some are remodeled into LDL and HDL, lipoproteins that are catabolized slowly and therefore dominate in plasma. The activity of LPL is regulated in a tissue-specific manner and this directs the destination of triglyceride transport. The enzyme binds fatty acids which provides a mechanism for product control of the reaction. When the tissue can no longer assimilate the fatty acids, the lipase reaction is stopped and the lipoprotein returns to the circulating blood. In addition to its catalytic action, lipoprotein lipase can also serve as a ligand for binding of lipoproteins to cell surfaces and to receptors. Hence, the lipase has a dual role in lipoprotein metabolism, mediating both unloading of triglycerides in extrahepatic tissues and particle catabolism in the liver.

Apolipoprotein C-II↗
PubMed1995

Intravenous lipid emulsions: removal mechanisms as compared to chylomicrons.

We have compared the metabolism of chylomicrons and a labeled emulsion, similar to those used for parenteral nutrition. Both were labeled in their triglyceride moieties and by a core label. It is known that chylomicron triglycerides are cleared by two processes: removal of triglycerides from the particles through lipolysis and removal of whole or partly lipolyzed particles. It has been proposed that emulsion droplets are cleared by the same pathways. After intravenous injection to postprandial rats, triglycerides were cleared less rapidly from the emulsion than from the chylomicrons (half-lives of 6.4 and 4.0 min), whereas the core labels were cleared at the same rate (half-lives around 7.5 min). This suggests that there was less lipolysis of the emulsion droplets which was further supported by the finding that less label appeared in the plasma free fatty acids (FFA). In adipose tissue of fed rats given chylomicrons, the ratio between fatty acid and core label was above 6, showing that fatty acids had been taken up after lipoprotein lipase-mediated hydrolysis. In contrast, for rats given emulsion, that ratio was only 1.2 showing that nearly as much emulsion droplets as emulsion-derived fatty acids were present in the tissue. In the liver the ratio was 0.55 after chylomicrons but 0.93 after emulsion. In further support of more lipolysis, fatty acids were oxidized more rapidly from chylomicrons than from emulsion. These data suggest that a large fraction of the emulsion droplets was removed from plasma with little or no preceding lipolysis. A substantial proportion, more than 50%, of this uptake occurred in extrahepatic tissues.

Animals↗
PubMed1994

Effect of protamine on lipoprotein lipase and hepatic lipase in rats.

The polycation protamine impedes the catabolism of triglyceride-rich lipoproteins and this has been suggested to be due to intravascular inactivation of lipoprotein lipase. We have made intravenous injections of protamine to rats and found that both lipoprotein lipase and hepatic lipase activities were released to plasma. The effect of protamine was more short-lived than that obtained by injection of heparin. The release of hepatic lipase by protamine was as effective as the release by heparin, while the amount of lipoprotein lipase released by protamine was only about one-tenth of that released by heparin. This was not due to inactivation of lipoprotein lipase, since injection of an excess of heparin 10 min after injection of protamine released as much lipoprotein lipase activity to plasma as in controls. The results in vivo differed from those obtained in model experiments in vitro. Protamine was able to almost quantitatively release both lipoprotein lipase and hepatic lipase from columns of heparin-agarose. The displacement was dependent on the total amount of protamine that had passed over the column, indicating that it was due to occupation by protamine of all available binding sites. Our results in vivo showed that the binding sites for lipoprotein lipase were not blocked as efficiently as those for hepatic lipase, indicating that the binding structures were not identical. It was concluded that the impaired turnover of lipoproteins by protamine probably was due to prevention of binding of the lipoproteins to endothelial cell surfaces rather than to impaired lipase function.

Animals↗
PubMed1994

Postprandial lipoproteins and progression of coronary atherosclerosis.

The relations between triglyceride-rich lipoproteins, alimentary lipaemia and coronary heart disease (CHD) have remained obscure and much debated. We studied the basal and postprandial plasma levels of chylomicron remnants and very low density lipoproteins (VLDL) of varying particle size in 32 male postinfarction patients (mean (S.D.) age 48.8 (3.2) years) and in 10 age-matched control men. The selective quantification of postprandial intestinal and hepatic lipoproteins was accomplished by determining apolipoproteins B-48 and B-100 in lipoprotein subfractions of Svedberg flotation (Sf) rates > 12 before and 3, 6 and 12 h after an oral fat load. Since all patients had undergone two coronary angiographies with an intervening time interval of around 5 years, lipoprotein fractions were examined in relation to the global severity as well as the rate of progression of coronary lesions. The postprandial plasma levels of small chylomicron remnants (Sf 20-60 apolipoprotein B-48) were found to relate distinctly to the rate of progression of coronary lesions between the angiographies (r = 0.51, P = 0.01). Adjustment for the possible confounding effect of the HDL cholesterol and dense LDL apolipoprotein B concentrations did not substantially alter the strength of this association. Neither the increment of plasma triglyceride during the postprandial period nor the concentrations of other lipoprotein fractions closely reflected the amount of small chylomicron remnants in the circulation or correlated with progression of coronary lesions. Our data suggest that small chylomicron remnants are implicated in the progression of coronary artery disease.

Apolipoprotein B-100↗
PubMed1994

Metabolism of emulsions containing medium- and long-chain triglycerides or interesterified triglycerides.

This study compares the clearing and metabolism of three different lipid emulsions. They had the same phospholipid emulsifier and similar particle sizes. In one (LLL) the core component was long-chain triglycerides (TG), the second (MMM/LLL) contained equal molar amounts of medium- and long-chain TG, the third (MLM) contained synthetic TG with medium-chain (M) fatty acids in the 1,3-positions and a long-chain (L) fatty acid in the 2-position. In model experiments with bovine lipoprotein lipase, the MMM component was hydrolyzed preferentially in the MMM/LLL emulsion so that the initial products were M fatty acids and M monoglycerides. The MLM emulsion, in contrast, gave M fatty acids and formation of L-MG (monoglyceride) throughout hydrolysis. For in vivo studies [3H]oleic acid was incorporated into the emulsion TG as marker for the long-chain component. After bolus injection to rats, the MMM/LLL and MLM emulsions were cleared more rapidly than the LLL emulsion. This was true at all TG loads studied (4-64 mg for a 200 g rat). The labeled oleic acid was oxidized somewhat more rapidly when administered in the MLM emulsion compared to the MMM/LLL emulsion. There were only slight differences in tissue distribution of label. Hence, differences in in vivo metabolism of the long-chain fatty acids were small compared to the marked differences in TG structure and in patterns of product release during in vitro lipolysis.

Animals↗
PubMed1993

Assembly of lipoprotein lipase in perfused guinea-pig hearts.

It has been suggested that lipoprotein lipase (LPL) can be assembled into its catalytically active dimeric form only after its oligosaccharide chains have been processed in the Golgi. To study this in a complete organ, LPL was metabolically labelled with [35S]methionine in perfused guinea-pigs hearts. After 10 min pulse-labelling, LPL protein was eluted as two peaks from heparin-agarose: peak 1 at about 0.65 M NaCl, peak 2 at about 0.95 M NaCl. Catalytic activity was associated only with peak 2. Model studies with bovine LPL showed that active dimeric LPL is eluted in peak 2, but after treatments that dissociate the enzyme into inactive monomers it is eluted in peak 1. Pulse-labelled LPL in both peak 1 and peak 2 was fully sensitive to treatment with endoglycosidase (Endo) H. With chase, peak 1 disappeared and peak 2 acquired resistance to Endo H. These findings suggest that core glycosylated LPL is assembled into dimers already in the endoplasmic reticulum and that processing of the oligosaccharide chains occurs after dimerization.

Animals↗