Is the glucocorticoid-induced hypertriglyceridemia in uremic rats caused by decreased tissue lipoprotein lipase activity?

The glucocorticoid-induced hypertriglyceridemia in uremic rats is partly due to defective removal of triglyceride (Tg)-rich lipoproteins. To determine whether this was due to decreased lipoprotein lipase (LPL), the key enzyme involved in the hydrolysis of Tg-rich lipoproteins, the LPL activity in soleus, heart and adipose tissue and the triglyceride secretion rates (TgSR) of uremic rats treated with Triamcinolone or placebo were studied. Sprague-Dawley rats were made uremic by a 2-stage 5/6 nephrectomy and studied three weeks later. During the 3rd week, one group was treated with a five day course of Triamcinolone (0.5 mg/kg body weight i.m.) and the other given an equal volume of saline. Triamcinolone aggravated the hypertriglyceridemia in uremic rats. This was associated with an increase in soleus and heart LPL with no change in adipose tissue LPL. The TgSR was also increased in the Triamcinolone-treated rats. These data suggest that decreased LPL activity is not the cause of hypertriglyceridemia in these rats.     

Tissue lipoprotein lipase,serum, and urinary lipids and lipoproteins in experimental glomerulonephritis of rats (Heymann's nephritis)

Serum and urinary cholesterol, triglycerides, high-density lipoproteins, and tissue lipoprotein lipase levels were measured in a group of rats in which experimental glomerulonephritis (EGN) was induced by an injection of renal tubular antigen in Freund's complete adjuvant. Progressively increasing proteinuria beginning after approximately the eighth week was associated with a progressive increase in the levels of serum cholesterol, triglycerides, and high-density lipoprotein cholesterol. Significant lipiduria occurred at the ninth week. Lipoprotein electrophoresis of concentrated urine showed the presence of a band with alpha lipoprotein (high-density lipoprotein) mobility. Eleven weeks after disease induction, the rats were killed and the tissue levels of lipoprotein lipase were measured. A homogenized preparation of the heart, liver, adipose tissue, and skeletal muscle using [¹⁴C]triolein as substrate was used. Nephrotic rats had less than half the myocardial lipoprotein lipase levels of controls (2099 ± 420 and 962 ± 142 (mean ± SD) nm free fatty acids/mg tissue/hr, respectively; P < 0.05). Hepatic, skeletal muscle, and adipose tissue lipoprotein lipase levels were not significantly different in the two groups of rats.These results document the potential usefulness of the rat (EGN) model for further studies in lipoprotein metabolism in nephrotic syndrome. The significance and pathogenesis of reduced myocardial lipoprotein lipase requires further investigation.     

Relationship of lipoprotein lipase and hepatic triacylglycerol lipase activity to serum adiponectin levels in Japanese hyperlipidemic men.

OBJECTIVE: The aim of this study was to determine how lipoprotein lipase (LPL) and hepatic triacylglycerol lipase (HTGL) activity relate to serum adiponectin levels. RESEARCH DESIGN AND METHODS: Fifty-five hyperlipidemic Japanese men were recruited for this study. LPL and HTGL activity in post-heparin plasma (PHP) was measured using Triton X-100 emulsified-[14C] triolein. The remaining activity in the presence of 1M NaCl was defined as HTGL activity. Serum adiponectin levels were determined by an enzyme-linked immunosorbent assay system. RESULT: LPL activity had a positive relationship with HDL2, but had no relation with HDL3, while HTGL had positive relationship with HDL3, but had no relationship with HDL2. LPL activity showed a positive relationship [r = 0.345, p = 0.010] to serum adiponectin levels, while and HTGL activity showed an inverse relationship [r = - 0.365 p = 0.006]. Multiple regression analysis with LPL and HTGL as dependent variables and age, BMI, serum adiponectin and the homeostasis model assessment of insulin resistance (HOMA-IR) as independent variables showed LPL and HTGL's association to adiponectin did not persist after adjustments for these covariants. However, the association of LPL activity to HOMA-IR was found to persist after adjustments of age, BMI, and serum adiponectin. CONCLUSIONS: There was a co-linearity between insulin sensitivity and adiponectin as well as insulin sensitivity and LPL/HTGL activity.     

Very low density lipoproteins and lipoprotein lipase in serum of rats deficient in essential fatty acids

Rats fed a diet deficient in essential fatty acids have a low level of serum very low density lipoproteins (VLDL). It was found that after intraperitoneal injection of heparin, deficient rats had a higher level of lipoprotein lipase activity in their plasma than did normal rats. VLDL isolated from serum of normal and deficient rats were compared as substrates for postheparin lipase of rat plasma. There was no significant difference in V(max) between the two preparations of lipoproteins, but the apparent K(m) for lipoproteins from deficient animals was significantly less than that for normal animals. These observations suggest that the low concentration of VLDL in deficient rats may be explained (a) by an increased activity of lipoprotein lipase in the tissues of these animals and (b) by the VLDL of deficient rats being more rapidly hydrolyzed at low concentrations by lipoprotein lipase than VLDL from normal rats.     

Changes in brown adipose tissue lipoprotein lipase activity and lipogenesis rate during pregnancy and lactation in the rat

Brown fat lipoprotein lipase activity did not change in the first two weeks of pregnancy whereas it decreased on day 18 of gestation and was lower during late pregnancy and lactation. Fatty acid synthesis rate, measured in vivo with (3H)H2O, showed a progressive increase until day 18 of gestation followed by a decrease on day 20 of pregnancy and a reduced lipogenesis rate throughout lactation. The early reduction in the pathways of fatty acid uptake and synthesis in brown fat during the breeding cycle of the rat suggests the possibility that a decline in the substrate supply was a factor contributing to the reduced thermogenic activity of brown adipose tissue after parturition.     

Experimental hyperthyroidism in man: effects on plasma lipoproteins, lipoprotein lipase and hepatic lipase

We have studied the effects of triiodothyronine administration (20-40 micrograms three times daily over one week) in six healthy young men, on the activities of lipoprotein lipase and hepatic lipase and on plasma lipoprotein concentrations. Hepatic lipase activity in post-heparin plasma rose by 46 +/- 25% (p less than 0.025), whereas the activity of lipoprotein lipase did not change significantly. Plasma cholesterol concentrations decreased by about 20% (p less than 0.025), whereas there was no change in plasma triglyceride levels. The fall in plasma cholesterol could be accounted for by a reduction of HDL cholesterol (-11%, p less than 0.025) as well as LDL cholesterol (-27%, p less than 0.025). The data emphasize the role of hepatic lipase in the lipoprotein alterations associated with thyroid dysfunction.     

Serum leptin concentrations in patients with combined hyperlipidemia: relationship to serum lipids and lipoproteins

Leptin is a protein hormone produced predominantly by adipocytes. Serum leptin concentrations in healthy individuals positively correlate with the body fat content and body mass index, i.e. they are higher in obese than in lean subjects. The relations between serum leptin concentration and serum lipids and lipoproteins is not yet clear. The aim of our study was to compare serum leptin concentrations in 22 randomly selected patients with untreated combined hyperlipidemia and 19 healthy control subjects matched for age and the body mass index. The relationship was studied between serum leptin concentrations and serum lipids (total, HDL, LDL cholesterol and triglycerides) and lipoproteins (lipoprotein (a), apolipoprotein B). It was found that serum leptin levels in patients with combined hyperlipidemia did not significantly differ from those of control subjects (6.69+/-4.3 vs 5.78+/-3.2 ng.ml(-1)). Serum leptin concentrations in both groups correlated positively with the body mass index. The relationship between leptin concentrations and lipid or lipoprotein levels found in any of the studied groups was not statistically significant. We conclude that serum leptin concentrations in patients with combined hyperlipidemia as well as in healthy control subjects reflect the body fat content and have no significant relation to serum lipids or lipoproteins.     

Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder with a frequency of 1-2% in the population. In addition to the hypercholesterolemia and/or hypertriglyceridemia that affected individuals exhibit, small, dense LDL particles and decreased HDL-cholesterol levels are traits frequently associated with FCH. Recently, we reported that families with FCH and families enriched for coronary artery disease (CAD) share genetic determinants for the atherogenic lipoprotein phenotype (ALP), a profile presenting with small, dense LDL particles, decreased HDL-cholesterol levels, and increased triglyceride levels. Other studies in normolipidemic populations have shown that the hepatic lipase (HL) gene is linked to HDL-cholesterol levels and that a polymorphism within the HL promoter (-514C-->T) is associated with increased HDL-cholesterol levels as well as larger, more buoyant LDL particles. In the present study, we tested whether the HL gene locus also contributes to ALP in a series of Dutch FCH families using nonparametric sibpair linkage analysis and association analysis. Evidence for linkage of LDL particle size (P < 0.019), HDL-cholesterol (P < 0.003), and triglyceride levels (P < 0.026) to the HL gene locus was observed. A genome scan in a subset of these families exhibited evidence for linkage of PPD (LOD = 2.2) and HDL-cholesterol levels (LOD = 1.2) to the HL gene locus as well. The -514C-->T promoter polymorphism was significantly associated (P < 0.0001) with higher HDL-cholesterol levels in the unrelated males of this population, but not in unrelated females. No association was observed between the polymorphism and LDL particle size or triglyceride levels. Our results provide support that ALP is a multigenic trait and suggest that the relationship between small, dense LDL particles, HDL-cholesterol, and triglyceride levels in FCH families is due, in part, to common genetic factors.     

Effect of two-week ethanol administration on lipoprotein lipase activity and blood serum lipids in the rat

Influence of ethanol administration on adipose tissue lipoprotein lipase activity, serum lipids in the rat. Intoxication caused a decrease of lipoprotein lipase activity. In some animals a rise of serum high density lipoprotein cholesterol was observed which correlated positively with the content of cytochrome P-450 in the liver.     

Effect of monosodium glutamate treatment during neonatal development on lipogenesis rate and lipoprotein lipase activity in adult rats.

Monosodium glutamate (MSG) has been shown to alter several neuroendocrine functions in neonatally treated rats. To evaluate possible alterations in lipogenesis rate and lipoprotein lipase (LPL) activity, male and female rats were injected during the neonatal period with MSG or saline (controls). In male MSG rats, an increase in lipogenesis of liver and retroperitoneal adipose tissues was observed. Triton WR 1339 (an LPL inhibitor) administration decreased retroperitoneal lipogenesis in these animals. In female rats, MSG-treatment increased lipogenesis only in gonadal and retroperitoneal adipose tissues. No change was observed in hepatic lipogenesis and the Triton administration did not change retroperitoneal lipogenesis. LPL activity was increased in the gonadal and retroperitoneal adipose tissues in male and female MSG-treated rats. These data suggest that there is a specific sex-dependent response in the development of MSG-induced obesity.     

Relationship of lipoprotein lipase activity to triglyceride uptake in adipose tissue

Fasted rats injected with actinomycin or fed glucose show increased lipoprotein lipase activity of epididymal adipose tissue. Data from the actinomycin-treated animals showed a direct correlation between the lipoprotein lipase activity and the uptake of lipoprotein triglyceride by the epididymal fat pad in vitro and in vivo. Data from the animals fed glucose confirmed these findings in vitro. These data strongly suggest that lipoprotein lipase plays a major role in triglyceride deposition in adipose tissue.     

Glucose tolerance, plasma lipoproteins and tissue lipoprotein lipase activities in body builders

Oral glucose tolerance, insulin binding to erythrocyte receptors, serum lipids, and lipoproteins, and lipoprotein lipase activities of adipose tissue and skeletal muscle were measured in nine body builders (relative body weight (RBW) 118 +/- 4%), eight weight-matched (RBW 120 +/- 5%) and seven normal-weight controls (RBW 111 +/- 3%). The body builders had 50% higher relative muscle mass of body weight (% muscle) and 50% smaller relative body fat content (% fat) than the two other groups (P less than 0.005). Maximal aerobic power was comparable in the three groups. In the oral glucose tolerance test (OGTT), blood glucose levels, and plasma insulin levels were lower (P less than 0.05) in the body builders than in weight-matched controls. Insulin binding to erythrocytes was similar in each group. On the basis of multiple linear regression analysis, 87% of the variation in plasma insulin response could be explained by body composition (% muscle and % fat) and VO2max. Plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL) triglyceride concentrations were significantly lower in the body builders than in weight-matched controls. In comparison with the normal-weight group, the body builders had a lower total cholesterol level. High density lipoprotein (HDL) cholesterol, its subfractions (HDL2 and HDL3 cholesterol) and lipoprotein lipase (LPL) activities of adipose tissue and skeletal muscle were comparable in all three groups. Partial correlation analysis showed a positive relationship between plasma total triglyceride, total cholesterol and LDL cholesterol on the other hand and the % fat on the other.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in lipoprotein lipase activity in the adipose tissue and heart of non-lethally X-irradiated rats

After 16 h nocturnal deprivation of food, male Wistar rats were irradiated by a single whole body dose of 2.40 Gy X-rays. Both the irradiated and sham-irradiated (control) rats were pair-fed for the first six days after irradiation, but for the rest of the time they were fed ad libitum. Lipoprotein lipase activity (LPLA) in the adipose tissue fell between 24 and 48 h; LPLA in the heart fell at 24 h and 21 days and rose on the 14th days. The serum triacylglycerol concentration rose between 24 and 72 h. Comparison with the fed control group showed LPLA in adipose tissue to be reduced at 6 and 72 h and on the 28th day and raised between the 7th and the 14th day. In the heart it was raised at 1 h and between 72 h and the 14th day, it was reduced on the 21st day and rose on the 35th day. The triacylglycerol concentration was raised between 48 and 72 h and on the 28th day. Pair-feeding after non-lethal X-irradiation allowed more exact differentiation of the specific effect of ionizing radiation on LPLA in the adipose tissue and heart at the early post-irradiation intervals.     

The significance of changes in tissue clearing-factor lipase activity in relation to the lipaemia of pregnancy

1. The concentration of triglyceride fatty acid in the plasma of the pregnant rat rises to a maximum 2-4 days before parturition. Thereafter there is a rapid decline in the concentration to near normal values at parturition. 2. A similar increase occurs in animals fed on a diet low in fat. There is no increase in food consumption at the time when the triglyceride fatty acid concentration in the plasma is at its peak. 3. Rates of entry of triglyceride fatty acid into the blood during pregnancy have been estimated from the rate of accumulation of triglyceride in the plasma of animals injected with a non-ionic detergent, Triton. A progressive increase occurs in the entry rate as the body weight increases throughout pregnancy. Expressed per constant body weight, the entry rate does not change significantly. 4. Adipose-tissue clearing-factor lipase activity is low at the time when the plasma triglyceride fatty acid concentration is raised. Activity of the enzyme in heart, lung and diaphragm is unchanged. 5. It is suggested that the ;lipaemia of pregnancy' may be due to diminished uptake of triglyceride fatty acids by adipose tissue, and, further, that the disappearance of the lipaemia may be due to increased uptake of triglyceride fatty acids by the mammary gland.     

Effects of four different single exercise sessions on lipids, lipoproteins, and lipoprotein lipase

The purpose ofthis study was to determine the threshold of exercise energyexpenditure necessary to change blood lipid and lipoproteinconcentrations and lipoprotein lipase activity (LPLA) in healthy,trained men. On different days, 11 men (age, 26.7 ± 6.1 yr; bodyfat, 11.0 ± 1.5%) completed four separate, randomly assigned,submaximal treadmill sessions at 70% maximalO₂ consumption. During eachsession 800, 1,100, 1,300, or 1,500 kcal were expended. Compared withimmediately before exercise, high-density lipoprotein cholesterol(HDL-C) concentration was significantly elevated 24 h after exercise(P < 0.05) in the 1,100-, 1,300-, and 1,500-kcal sessions. HDL-C concentration was also elevated(P < 0.05) immediately after and 48 h after exercise in the 1,500-kcal session. Compared with values 24 hbefore exercise, LPLA wassignificantly greater (P < 0.05) 24 h after exercise in the 1,100-, 1,300-, and 1,500-kcal sessions andremained elevated 48 h after exercise in the 1,500-kcal session. Thesedata indicate that, in healthy, trained men, 1,100 kcal of energyexpenditure are necessary to elicit increased HDL-C concentrations.These HDL-C changes coincided with increased LPLA.

     

Binding of low density lipoproteins to lipoprotein lipase is dependent on lipids but not on apolipoprotein B

Lipoprotein lipase (LPL) efficiently mediates the binding of lipoprotein particles to lipoprotein receptors and to proteoglycans at cell surfaces and in the extracellular matrix. It has been proposed that LPL increases the retention of atherogenic lipoproteins in the vessel wall and mediates the uptake of lipoproteins in cells, thereby promoting lipid accumulation and plaque formation. We investigated the interaction between LPL and low density lipoproteins (LDLs) with special reference to the protein-protein interaction between LPL and apolipoprotein B (apoB). Chemical modification of lysines and arginines in apoB or mutation of its main proteoglycan binding site did not abolish the interaction of LDL with LPL as shown by surface plasmon resonance (SPR) and by experiments with THP-I macrophages. Recombinant LDL with either apoB100 or apoB48 bound with similar affinity. In contrast, partial delipidation of LDL markedly decreased binding to LPL. In cell culture experiments, phosphatidylcholine-containing liposomes competed efficiently with LDL for binding to LPL. Each LDL particle bound several (up to 15) LPL dimers as determined by SPR and by experiments with THP-I macrophages. A recombinant NH(2)-terminal fragment of apoB (apoB17) bound with low affinity to LPL as shown by SPR, but this interaction was completely abolished by partial delipidation of apoB17. We conclude that the LPL-apoB interaction is not significant in bridging LDL to cell surfaces and matrix components; the main interaction is between LPL and the LDL lipids.