Lipoprotein lipase and hepatic lipase activity after heparin administration in abetalipoproteinemia and hypobetalipoproteinemia

The purpose of this study was to examine whether an absence of triglyceride-rich lipoproteins (chylomicrons and very-low-density lipoproteins) in plasma is associated with any changes in the enzyme activity of lipoprotein lipase or hepatic lipase after heparin administration. To study this, the activities of hepatic lipase and lipoprotein lipase were determined in control subjects, in two patients with heterozygous hypobetalipoproteinemia, and in three patients with phenotypic abetalipoproteinemia after administration of heparin. Both enzymes showed normal activity in the patients with hypobetalipoproteinemia, but showed consistently reduced activity in the patients with abetalipoproteinemia. Hepatic lipase activity in plasma samples from these three patients obtained 15 minutes after intravenous injection of heparin was 55%, 87%, and 46% of that of the controls, whereas corresponding values in plasma samples obtained 30 minutes after heparin were 47%, 70%, and 57%, respectively. Lipoprotein lipase activity in the three patients with abetalipoproteinemia was 46%, 29%, and 34% of that of the controls in the samples obtained 15 minutes after heparin injection, whereas the values obtained after 30 minutes were 53%, 64%, and 47% of that of the controls. We conclude that an inherent absence of triglyceride-rich lipoproteins, as occurs in abetalipoproteinemia, is associated with reduced enzyme activity of both hepatic lipase and lipoprotein lipase in plasma after heparin administration.     

Lipoprotein lipase activity in human adipose tissue during induced hypertriglyceridaemia.

Needle biopsies of adipose tissue and blood samples were obtained before and at short intervals after a "bolus" injection of 10% Intralipid. Lipoprotein lipase activities were measured in acetone--ether extracts of the tissue samples. Levels of serum triglyceride began to fall less than 5 min after the injection of the Intralipid with a half-life of 20 min. During this time interval, no significant changes were observed in the activities of lipoprotein lipase in adipose tissue. A patient with a severe hypertriglyceridaemia (Type V) underwent plasma exchange with a reduction in serum triglyceride levels from 11 to 4 mm/l. There was a parallel fall in adipose tissue lipoprotein lipase activity. We conclude that lipoprotein lipase in adipose tissue is unaltered during experimental hypertriglyceridaemia and that the activity of the enzyme in adipose tissue is probably not reduced as a secondary feature of an elevated plasma triglyceride level.     

Short-term effects of ACTH on the low-density lipoprotein receptor mRNA level in rat and hamster adrenals.

Low-density lipoprotein (LDL) receptor mRNA was found in both rat and hamster adrenals. Within 30 min after ACTH administration a significant increase in the levels of both LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) mRNAs was observed in rat adrenals; these levels remained increased for up to 240 min. The increase in the levels of LDL receptor and HMG-CoA reductase mRNAs produced by ACTH was reduced by co-administration of aminoglutethimide while, at the same time, the adrenal cholesterol content of rats treated with both aminoglutethimide and ACTH was significantly increased compared with that in groups treated with ACTH alone. Cycloheximide also induced increased levels of rat adrenal mRNAs for LDL receptor and HMG-CoA reductase, but this effect was not additive with that of ACTH. These results suggest that, in the rat, the short-term effect of ACTH on the levels of mRNAs for the LDL receptor and HMG-CoA reductase is similarly controlled and might be mediated through changes in the adrenal cholesterol content. In the hamster adrenal, however, no significant fluctuations were found in the level of LDL receptor mRNA, although a marked increase was found in the level of HMG-CoA reductase mRNA, 2 h after ACTH administration. This indicates that an important effect of ACTH on cholesterol metabolism in the hamster adrenal is at the level of HMG-CoA reductase. In the hamster, therefore, where the main source of cholesterol for the adrenal gland is de-novo synthesis, it seems that a complex mechanism is involved in the control of LDL receptor gene expression.     

The fetal adrenals of the rat: correlations between growth, cytology, and hormonal activity, with and without ACTH deficiency.

Growth, ultrastructure, and corticosterone content were studied in the adrenals of rat fetuses in late pregnancy, between Days 19 and 21. In the fetuses of intact mothers, the hypophysial corticostimulating activity decreased between Days 19 and 21. Ablation of the fetal hypothalamus by total removal of the brain, leaving the hypophysis in situ (encephalectomy), induced atrophy of the adrenals, changes in adrenal ultrastructure, and decrease in the adrenal corticosterone content. Such modifications were also observed in response to the ablation of the pituitary gland by decapitation. The hypothalamus was involved in the control of ACTH release in late pregnancy. When mothers were adrenalectomized on Day 14, in the absence of hypothalamic tissue, the pituitary gland of the encephalectomized fetuses showed some corticostimulating activity; indeed, the adrenals of these fetuses were heavier on Day 21 than those of the decapitated fetuses but smaller than those of the littermate controls, and the adrenal corticosterone content was also greater than in the decapitated but less than in the controls. Encephalectomy induced modifications in adrenal cytology less marked than those induced by decapitation. These data suggest that the pituitary gland and the hypothalamo-hypophysial complex are the sites of the corticosteroid-induced inhibition of the corticostimulating activity of the fetal hypophysis.     

Lipoprotein lipase in relation to inflammatory activity in rheumatoid arthritis

Objective. To evaluate the impact of chronic inflammation on lipoprotein lipase (LPL) levels and triglyceride metabolism in patients with rheumatoid arthritis (RA). Design. Plasma levels of LPL activity and mass before and after heparin were determined in post-menopausal women with active RA and in controls. The results were related to lipid levels and inflammatory variables. The LPL activity and mass together with triglyceride levels were also measured before and 6 h after an oral fat load. Setting. The study was performed on in- and out-patients at a University Rheumatology clinic. The controls came from the same reference area. Subjects. Altogether 17 consecutive post-menopausal female patients with RA and 16 age and sex matched controls were enrolled for the initial determination of LPL. Fifteen of the patients and 15 of the controls agreed to take part in the fat load. Of these, one patient and one control were excluded. Main outcome measures. LPL determination: basal levels and post-heparin levels of LPL activity and mass. Correlations between LPL and blood lipids (cholesterol, triglycerides), lipoprotein levels (high density lipoprotein, HDL; low density lipoprotein, LDL), erythrocyte sedimentation rate (ESR) acute phase proteins (orosomucoid, haptoglobin, fibrinogen mass) and cytokines (tumour necrosis factor α, TNF-α; interleukin 1β, IL-1β; and interleukin-6, IL-6). Fat tolerance test: LPL activity, mass and triglyceride levels before and 6 h after a per oral fat load. Results. Pre-heparin LPL mass (P<0.01) and activity (P<0.01) were significantly lower in the rheumatoid patients. Pre-heparin LPL mass showed no correlation to the lipid levels, but an inverse correlation to several inflammatory parameters; it was significant for orosomucoid (r_s=?0.63, P<0.05) and C-reactive protein (CRP) (r_s=?0.54, P<0.05) and close to significant for haptoglobin (r_s=?0.48, P=0.087) and IL-6 (r_s=?0.52, P=0.061). Six hours after a lipid load the LPL activity and mass were significantly lower in RA (P<0.05 and P<0.01, respectively) but the triglyceride level was not significantly different compared to controls. Conclusion. An inverse relationship exists between inflammatory status and pre-heparin LPL mass. Pre-heparin LPL mass reflects mainly the inactive monomeric fraction of LPL. This has been shown to hinder the uptake of remnant lipoprotein particles through competition with lipoprotein bound dimeric LPL for the LDL receptor-related protein (LRP receptor) on hepatocytes and macrophages in culture. A decrease of the level of monomeric LPL in plasma may thus be beneficial for remnant catabolism. The same mechanism may on the other hand increase macrophage uptake of lipids. This may not affect global lipid metabolism but may be important in driving the atherosclerotic process in the vessel wall.     

Lipoprotein lipase and its role in regulation of plasma lipoproteins and cardiac risk

For over 50 years, biologists and clinicians have studied lipoprotein lipase (LPL) and learned about its structure, function, cellular production, physiology, and human genetics. LPL is the principal enzyme that removes triglyceride from the bloodstream. It also determines plasma levels of high-density lipoprotein. Surprisingly, within the past several years, a number of new and unexpected proteins have been discovered that regulate the actions of LPL. These include the very low-density lipoprotein receptor, angiopoetin-like protein 3, and apolipoprotein A-V. In addition, mouse genetic studies have confirmed tissue culture findings of nonenzymatic roles of LPL both in lipid metabolism and atherogenesis. These basic observations are now being related to new information on human genetic polymorphism in this gene that is likely to affect clinical evaluation of lipoprotein disorders and cardiac risk.     

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.     

Lipoprotein lipase is produced, regulated, and functional in rat brain.

Lipoprotein lipase (LP lipase, triacylglycero-protein acylhydrolase EC 3.1.1.34) activity was found in four dissimilar brain regions (hypothalamus, cortex, cerebellum, and midbrain) of adult male rats. Progressive accumulation of LP lipase activity in cultured fetal rat hypothalamic cells was also observed, indicating de novo synthesis of the lipase. The brain LP lipase activity was serum-dependent and was inhibited by 1 M NaCl and by protamine sulfate. Kinetic analysis revealed an apparent Km of 0.79 mM very similar to that of rat adipose tissue LP lipase. That the lipase was functioning in the cultured brain cells was indicated by uptake and incorporation of radioactivity from tri[( 1-14C]oleoyl)glycerol into cellular triacylglycerols, and into more polar lipids, such as phosphatidylcholine. Furthermore, brain LP lipase activity in adult rats was decreased in all four regions examined, most significantly in the hypothalamus, after 72 hr of food deprivation. Thus, authentic LP lipase is present in adult rat brain and can be synthesized by isolated brain cells in vitro. LP lipase also mediates the uptake of triacylglycerol fatty acids and their subsequent incorporation into cellular lipids of cultured brain cells. Decreased brain LP lipase activity after fasting suggests that this enzyme may be regulated by metabolic or nutritional factors. Because the largest changes in LP lipase activity in response to food deprivation occurred in the hypothalamus, the enzyme may have a role in hypothalamic control of food intake or in body-weight regulation.     

Lipoprotein lipase activity in adipose tissue and skeletal muscle of runners: relation to serum lipoproteins.

Physically well-trained people generally have lower VLDL-triglyceride and higher HDL-cholesterol levels than sedentary subjects. To examine the underlying mechanisms of this lipoprotein pattern, we measured the lipoprotein lipase (LPL) activity in needle biopsy specimens of adipose tissue and skeletal muscle of competitive runners and of body weight-matched, physically less-active controls. The active sportsmen were either sprinters, whose training program consisted mainly of athletics of short duration or long distance runners undergoing a strenuous endurance exercise program. In sprinters (all males) the serum lipid and lipoprotein concentrations did not differ significantly from those of controls and the mean LPL activities in muscle and adipose tissue were also similar in these two groups. The long distance runners (both sexes), on the other hand, had higher means levels of HDL-cholesterol than the respective controls. The LPL-activity of both adipose tissue (p less than 0.05) and skeletal muscle (p less than 0.01) was significantly higher in male long distance runners than in control males. Female runners had higher muscle LPL activity than controls (p less than 0.01) but in adipose tissue the difference in LPL activity was not significant. Rough estimates calculated for LPL activity present in whole body adipose tissue and skeletal muscle indicated that total LPL activity was 2.3 times higher in male long distance runners and 1.5 times higher in female long distance runners than in the respective controls. In combined groups of male runners and controls, there was a highly significant positive correlation between the serum HDL-cholesterol level and the LPL activity of adipose tissue expressed per tissue weight (r = +0.72, p less than 0.001) or per whole body fat (r = +0.62, p less than 0.001). The group means of HDL-cholesterol and adipose tissue LPL activity in the five cohorts studied (male sprinters, distance runners and controls and female distance runners and controls) were also positively correlated (r = +0.94). It is concluded that endurance training is associated with an adaptive increase of LPL activity not only in skeletal muscle but also in adipose tissue. These changes are not observed in sprinters who are trained by exercises of shorter duration. The high HDL-cholesterol levels of physically well-trained people are probably accounted for, at least partly, by the increased LPL activity and the concomitant rapid turnover or triglyceride-rich lipoproteins.     

Lipoprotein alterations, hepatic lipase activity, and insulin sensitivity in subclinical hypothyroidism: response to L-T(4) treatment.

Subclinical hypothyroidism (sH) has been associated with atherosclerotic cardiovascular disease even in the absence of hypercholesterolemia. OBJECTIVE: Our study was designed to assess the hypothesis that other pro-atherogenic parameters, such as qualitative lipoprotein changes and insulin resistance, might be present in sH. DESIGN AND METHODS: Twenty-one sH women were compared to 11 female controls matched for body mass index, menopausal status, and age. Before and after 6 months of levothyroxine (L-T(4)) treatment, we determined total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apoB levels, hepatic lipase (HL) activity in postheparin plasma samples, the chemical composition and copper-induced oxidation in isolated LDL and homeostasis model assessment (HOMA), quantitative insulin sensitivity check index, and insulinogenic index. MAIN OUTCOME: Lipid profiles were similar between the two groups. No differences in LDL oxidability or the insulin sensitivity assessment parameters were found. HL activity was significantly lower in the sH patients: median (range), 13.1 (2.5-26.7) vs. 18.7 (7.9-28.1) micromol free fatty acids/mL, p < 0.04. The LDL-cholesterol/LDL-TG ratio was decreased in sH: 3.9 (1.8-5.5) vs. 4.7 (3.5-6.8), p < 0.02. HL negatively correlated with thyroid-stimulating hormone (TSH) levels (r = - 0.504, p < 0.01) and positively with LDL-cholesterol/LDL-TG (r = 0.46, p < 0.02). Posttreatment results for all these parameters did not differ significantly compared to baseline. CONCLUSIONS: Increased levels of TSH are associated to a decrease in HL activity, explaining our findings of an LDL particle rich in TG. This qualitative lipoprotein alteration suggests a pro-atherogenic pattern in sH. Treatment with L-T(4), however, did not correct the basal lipid derangement.     

Lipoprotein lipase secretion by human monocytes and rabbit alveolar macrophages in culture.

Human peripheral blood monocytes and rabbit alveolar macrophages secreted lipoprotein lipase during culture. Within hours after plating, lipoprotein lipase had accumulated in the culture medium of monocytes, and the rate of accumulation increased with time in culture. The initial rate of secretion of lipoprotein lipase by alveolar macrophages was higher than in monocytes but decreased after 8--10 hr to values similar to those expressed by monocytes cultured for the same length of time. The enzyme was characterized as lipoprotein lipase (triacylglycero-protein acylhydrolase, EC 3.1.1.34) on the basis of pH optimum (7.8--8.2 for monocytes, 8.1 for alveolar macrophages), dependence on apolipoprotein C-II for activity, inhibition by 0.3--0.5 M sodium chloride and protamine sulfate, and retention of a heparin-Sepharose gel. The expression of lipoprotein lipase secretion by human monocytes may have important implications with respect to the development of foam cells in the arterial wall during atherogenesis.     

Lipoprotein and hepatic lipase activity and high-density lipoprotein subclasses after cardiac transplantation

Atherosclerosis is the leading obstacle to long-term survival in cardiac transplant patients. Increases in plasma triglycerides and lipoprotein cholesterol levels occur after transplantation that may contribute to transplant atherosclerosis. The etiology of this increase is unclear. We investigated the interaction of immunosuppressive medications with plasma triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, the HDL subclasses HDL2 and HDL3 cholesterol, and hepatic and lipoprotein lipase activity in 72 consecutive cardiac transplant patients compared to 51 healthy control subjects. In the transplantation group, greater concentrations of plasma triglyceride (80%, p less than 0.001), LDL cholesterol (16%, p less than 0.005) and hepatic lipase activity (100%, p less than 0.001) were noted, whereas lipoprotein lipase activity was noted to be significantly lower (124%, p less than 0.001). No difference was detected in HDL, HDL2, or HDL3 cholesterol. Cyclosporine dose was significantly associated with hepatic lipase activity (r = 0.33, p less than 0.02) and inversely associated with lipoprotein lipase activity (r = -0.28, p less than 0.05). Lipoprotein lipase activity after transplantation correlated inversely with triglycerides (r = -0.36, p less than 0.002) and positively with HDL cholesterol (r = 0.23, p less than 0.05) and HDL2 cholesterol (r = 0.29, p less than 0.05). Hepatic lipase activity correlated inversely with LDL cholesterol (r = -0.21, p less than 0.08). In multiple regression analysis, cyclosporine dose was the major source of variation in hepatic lipase activity.     

Steroid fatty acid esters in adrenals and plasma: effects of ACTH

The presence and production of 5-ene-steroid fatty acid esters (SFA) has been previously reported in bovine adrenals. A study was conducted, using a series of chromatographic procedures and radioimmunoassays, to determine the levels of SFA in adrenals from man, cattle, dog, rat and guinea-pig, and to assess, in both rats and guinea-pigs, the effect of ACTH on SFA production by adrenals and their subsequent secretion into the circulation. The effects of ACTH on plasma SFA and non-conjugated steroid levels were also investigated in human subjects. Our data indicated that adrenal pregnenolone fatty acid ester (PREG-FA) levels were below 40% of PREG levels in cattle, dog, rat and guinea-pig while, in man, PREG-FA levels were threefold those of PREG. A large proportion of dehydroepiandrosterone (DHEA) and 5-androstene-3 beta, 17 beta-diol were present as fatty acid ester derivatives in the adrenals of all species, with the exception of cattle. In both rats and guinea-pigs, administration of ACTH caused a sharp increase in adrenal PREG of approximately threefold which lasted for 6 h, while the concentration of adrenal PREG-FA was slightly increased for a short time. In plasma, however, a marked rise in PREG-FA occurred, while the changes in PREG levels were much lower than those of its acylated counterpart. In man, PREG and DHEA concentrations were rapidly stimulated two-fold in the first 30 min following the administration of ACTH, while PREG-FA and DHEA-FA levels were increased by approximately 2.5-fold (P less than 0.01) at 120 and 180 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipoprotein lipase activity of adipose tissue and skeletal muscle in insulin-deficient human diabetes

Summary We have previously shown that lipoprotein lipase (LPL) activity of tissues is an important determinant not only of plasma VLDL levels but also of HDL-cholesterol. Studies were designed to investigate whether the serum lipoprotein alterations in uncontrolled insulin-deficient diabetes can be accounted for by changes in LPL activity of tissues. The heparin-releasable LPL activity was determined from biopsy samples of adipose tissue and skeletal muscle in 16 patients with newly detected untreated insulin-deficient diabetes and in 16 age-, sex- and body weight-matched healthy control subjects. Repeat assays were carried out after the patients had been on insulin treatment for an average of two weeks and when the diabetes was well controlled. When untreated the patients had increased concentrations of triglycerides and cholesterol in whole serum and in VLDL and LDL while the HDL cholesterol level was lower than that of controls (p<0.01). The cholesterol/triglyceride ratio in each of the three lipoproteins was similar in patients and controls. While untreated the diabetic patients had significantly reduced mean LPL activity both in adipose tissue (average 34% of control mean, p<0.001) and in skeletal muscle (average 45% of control mean, p<0.05). In the whole group HDL-cholesterol was positively correlated with adipose tissue LPL activity (r=+0.58, p<0.001) while log serum total triglyceride and log VLDL-triglyceride showed significant negative correlations with LPL activity of both adipose tissue and skeletal muscle. After initiation of insulin treatment the LPL activity increased significantly (p<0.01) in both tissues but was still subnormal after 2 weeks. At the same time the VLDL and LDL concentrations had returned to normal while the HDL-cholesterol remained low. The results suggest that the increase of VLDL and LDL triglyceride and the decrease of HDL-cholesterol present in uncontrolled insulin-deficient diabetes are, at least partly, accounted for by decreased LPL activity of tissues. The restoration of tissue LPL and of serum HDL-cholesterol by insulin are relatively slow processes. The results are consistent with the hypothesis that HDL-cholesterol concentration is dependent on the efficiency of removal of triglyceride-rich lipoproteins from the circulation.