Postheparin Lipolytic Activity Research Articles

Beneficial effects of fish liver preparations of sea bass (Lates calcarifer) versus gemfibrozil in high fat diet-induced lipid-intolerant rats.

Abnormal lipid metabolism is a main cause of dyslipidemia, which is a major risk factor for coronary heart disease and obesity and is even linked to diabetic-dyslipidemic complications. Fifteen days of high-fat feeding in Charles Foster rats resulted in a significant increase in baseline serum lipid levels accompanied by pronounced dyslipidemia. Treatment with fish liver preparations (FLPs) from sea bass and the standard drug gemfibrozil produced a lowering of serum lipids and glucose levels, along with a fall in very-low-density and low-density lipoprotein and an increase in high-density lipoprotein levels. Simultaneously, reactivation of plasma postheparin lipolytic activity (PHLA) and lecithin:cholesterol acyltransferase (LCAT) activity was also observed. A positive correlation was observed between low-density lipoprotein activity and fecal bile acid excretion, which was enhanced on treatment with FLPs and gemfibrozil, indicating the catabolic process for normal lipids and cholesterol homeostasis. These data suggest that FLPs and gemfibrozil not only lower lipid intolerance but also reduce diabetic-dyslipidemic complications by activating peroxisome proliferator-activated receptors (PPAR).

Down-regulation of lipoprotein lipase and VLDL receptor in rats with focal glomerulosclerosis

Patients and animals with nephrotic syndrome and those with chronic renal failure (CRF) often exhibit hypertriglyceridemia and impaired very low-density lipoprotein (VLDL) clearance. Imai rats that were originally derived from Sprague-Dawley rats develop spontaneous proteinuria, hyperlipidemia, progressive renal insufficiency and histologic changes of focal glomerulosclerosis (FGS), closely resembling human FGS. This study was undertaken to test the hypothesis that elevation of plasma triglyceride and VLDL concentrations in the Imai rats is associated with deficiency of lipoprotein lipase (LPL) and VLDL receptor which are the main pathways of triglyceride-rich lipoprotein clearance. Male Imai and Sprague-Dawley control rats were fed regular rat chow and studied at 10 and 34 weeks of age. Tissue LPL and VLDL-r protein abundance (Western analysis) and post-heparin lipolytic activity were determined. At 10 weeks of age, Imai rats showed mild proteinuria, moderate hyperlipidemia, normal creatinine clearance and blood pressure. By 34 weeks of age, the study animal exhibited severe proteinuria, marked hyperlipidemia, significant renal insufficiency and hypertension. This was associated with a severe progressive reduction in skeletal muscle and adipose tissue LPL and VLDL-r protein abundance and depressed plasma post heparin, lipolytic activity. Progressive hyperlipidemia in the Imai rats with spontaneous FGS is accompanied by severe combined LPL and VLDL-r deficiencies that can, in part, account for the associated hypertriglyceridemia and elevated plasma VLDL concentrations.

Effects of etofibrate upon the metabolism of chylomicron-like emulsions in patients with coronary artery disease

Slow chylomicron intravascular catabolism has been associated with coronary artery disease and screening for drugs that can speed-up this process can be important. In this study, the effects of etofibrate upon chylomicron metabolism was tested by determination of the plasma kinetics of a chylomicron-like emulsion model in 12 patients with coronary artery disease, aged 59±11 years, (total cholesterol: 240±41 mg/dl; triglycerides: 188±42 mg/dl) submitted to a randomized, crossover, double-blind, placebo-controlled study with administration of 1 g per day etofibrate or placebo for 1-month. A 1-month washout period was inserted between the treatment periods. Patients were intravenously injected a chylomicron-like emulsion doubly labeled with 14C-cholesteryl oleate and 3H-triolein at baseline and after treatments. After etofibrate treatment, there was decrease of total cholesterol and triglyceride plasma levels and a trend to increase high-density lipoprotein cholesterol plasma levels. Etofibrate elicited 62% enhancement of post-heparin lipolytic activity and 100% increase of 3H-triglyceride fractional clearance rate compared with placebo treatment. 14C-cholesterol ester fractional clearance rate was 260% greater after etofibrate than after placebo. Therefore, a potent effect of etofibrate on both chylomicron lipolysis and remnant removal was achieved, indicating that this drug can be used to improve this metabolism in future prospective studies.

Cardiovascular fitness, body composition, and lipoprotein lipid metabolism in older men.

Lipoprotein lipids in older individuals are affected by family history of coronary artery disease (CAD), obesity, diet, and physical activity habits. The relationship of obesity and physical fitness (VO2max) to lipoprotein lipids and postheparin lipases was examined in a cross-sectional study of 12 lean (LS) and 26 obese (OS) sedentary men and 18 master athletes (MAs) aged 65+/-1 years (mean +/- SE). The men were healthy, had no family history of CAD, and were weight stable on AHA diets at the time of study. VO2max was similar in LS and OS men but higher in the MAs. The OS men had a higher percentage of body fat (%BF), waist circumference, and waist:hip ratio (WHR) than the MA and LS men, but MA and LS men differed only in waist circumference. Total and LDL-C levels were comparable, but HDL-C, HDL2-C, and %HDL2b subspecies were higher in MAs than in OS and LS men, and in LS than in OS men. Triglyceride (TG) was similar in MAs and LS men but higher in OS men. Across groups, two multiple regression analyses models (VO2max, %BF, and WHR or waist circumference) showed that %BF and VO2max independently predicted HDL-C and HDL2, whereas WHR predicted TG (r2 = .45) more strongly than waist circumference (r2 = .39). Postheparin lipoprotein lipase activity (LPL) was comparable among groups and correlated independently with VO2max. Total postheparin lipolytic activity (PHLA), hepatic lipase activity (HL), and HL:PHLA ratio were similar in MAs and LS men but higher in OS men. In both multiple regression analysis models, only %BF predicted HL activity and the HL:PHLA ratio. The HL:PHLA ratio independently predicted HDL-C, HDL2-C, %HDL2b, %HDL3 subspecies, and the cholesterol:HDL-C ratio, whereas LPL activity predicted TG. Increased fitness and reduced total and abdominal fatness in MAs are associated with lower HL and higher LPL activities, which may mediate their higher HDL-C and lower TG levels relative to their sedentary peers.

Chylomicron metabolism in patients submitted to cardiac transplantation.

Development of coronary graft disease is the most important cause of late heart graft failure. Alterations in plasma lipid profile are frequent in heart transplant (HT) patients, but they seem not to be prominent. Currently, the metabolism of chylomicrons, the lipoproteins that carry dietary lipids absorbed by the intestine, was evaluated because chylomicron remnants are considered atherogenic. An emulsion labeled with 3H-triolein and 14C-cholesteryl oleate and known to mimic the metabolic behavior of chylomicrons was injected intravenously after a 12-hr fast into 34 HT patients, 24 patients with end-stage heart failure (ESHF), and 30 healthy normolipidemic subjects. The plasma disappearance curves of the radioisotopes were determined from blood samples collected over 1 hr. In some of the patients and in controls, in vitro postheparin lipolytic activity was measured and an oral fat load test with postprandial measurement of triglyceridemia was performed. Fractional clearance rate (in m(-1), median [25%; 75%]) of both emulsion 3H-triolein and 14C-cholesteryl oleate was extremely diminished in HT patients (HT: 0.0114 [0.0114; 0.0179] and 0.2x10(-8) [0.2x10(-8); 0.0041, respectively]; ESHF: 0.0226 [0.0223; 0.0568] and 0.0160 [0.0055; 0.0189]; control subjects: 0.0270 [0.0226; 0.0392] and 0.0090 [0.0042; 0.0180], respectively, P<0.05). HT patients also had reduced postheparin lipolysis and marked elevation of postprandial triglyceridemia compared with the controls. HT patients develop accumulation in the plasma of chylomicrons and their remnants. The observed alterations were so intense that they may suggest an important involvement of atherogenic chylomicron remnants in coronary graft disease.

STUDY OF THE HYPOLIPIDEMIC PROPERTIES OF PECTIN, GARLIC AND GINSENG IN HYPERCHOLESTEROLEMIC RABBITS

Experimental hypercholesterolemia and its modulation by some natural dietary supplements (pectin, garlic and ginseng) and by the drug gemfibrozil were studied. Experimental hypercholesterolemia was induced by feeding rabbits a 2% cholesterol-enriched diet for 28 days. Hypercholesterolemic rabbits were classified into five groups. One group did not receive treatments and served as a control hypercholesterolemic group. The other four groups were fed the cholesterol-enriched diet in conjunction with either 10% pectin, 2% garlic, 2% ginseng or 135 mg g−1b.w gemfibrozil in a daily oral dose. A normal group of rabbits fed a plain chow diet was also included in the study. The hypolipidemic effect of the above treatments was examined by estimating serum triglycerides (TG), total-, LDL- and HDL-cholesterol. Post-heparin total and hepatic lipase activities were estimated in post-heparin plasma obtained 10 min after an intravenous injection of heparin (200 IU kg−1b.w). In order to evaluate the antioxidant status of the rabbits, plasma malondialdehyde (MDA) level and erythrocyte superoxide dismutase (SOD) activity were measured. After killing, aorta from all rabbits were subjected to histopathological examination. Results of the study demonstrated that feeding the cholesterol-enriched diet caused a significant increase in total-, LDL-, and HDL-cholesterol, plasma MDA and post-heparin total and hepatic lipase activities. On the other hand, serum TG and erythrocyte SOD were not changed. Histopathological examination revealed marked alteration in the aortic wall with the appearance of large multiple atheromatous plaques. Both garlic and pectin were successful in a significant reduction of the hypercholesterolemia in a way comparable to gemfibrozil. Garlic was the only treatment that has antilipid peroxidative property. Erythrocyte SOD activity was not affected by hypercholesterolemia or by any of the treatments. Also, none of the treatments were able to modify the significant elevation of post-heparin lipolytic activities associated with the hypercholesterolemia or to significantly affect the serum triglycerides level. Finally, among the hypercholesterolemic groups that received treatments, the least changes in the aortic wall were shown in the animals of the gemfibrozil group. Slight degeneration was observed in the aorta of animals treated with pectin or garlic. Ginseng administration failed to exert any significant protection from the remarkable hypercholesterolemia or atherosclerosis associated with the cholesterol- enriched diet.

Gene expression of lipoprotein lipase in experimental nephrosis

Nephrotic syndrome (NS) is commonly associated with marked hypertriglyceridemia, impaired triglyceride-laden lipoprotein clearance, and reduced peripheral tissue uptake of triglycerides from chylomicrons. Lipoprotein lipase (LPL) is the rate-limiting step in triglyceride-rich lipoprotein metabolism. Earlier studies have demonstrated a marked reduction of plasma post-heparin lipolytic activity and LPL protein in NS. However, the effect of NS on gene expression of LPL has not been elucidated. We studied rats with puromycin aminonucleoside-induced NS and the placebo-injected control animals. Heart, soleus muscle, and fat body LPL activity, protein mass, and mRNA were measured and plasma lipid levels were quantitated. The NS group exhibited marked proteinuria, hypoalbuminemia, and hypertriglyceridemia. This was associated with significant reductions of LPL activity and immunodetectable protein in the heart, adipose tissue, and soleus muscle in the NS group. The reduction in LPL protein mass in the tissues tested was accompanied by a parallel reduction in LPL mRNA of the heart but not of either adipose tissue or skeletal muscle, suggesting translational or posttranslational modifications. A negative correlation was found between plasma triglyceride concentration and the LPL, activities of the tissues tested in the study population. Thus this study has revealed a significant down-regulation of tissue LPL protein in experimental NS. This phenomenon can, in part, account for hypertriglyceridemia, impaired catabolism of chylomicrons, and very low-density lipoprotein by peripheral tissues and decreased postheparin lipolytic activity in NS.

Effect of long-term exogenous hyperinsulinemia and fructose or glucose supplementation on triglyceride turnover in rats

We examined the effect of long-term (6 months) hyperinsulinemia on VLDL-triglyceride turnover in male Wistar rats. Hyperinsulinemia was induced in rats by daily s.c. injection of Ultralente insulin (6 U/day at 19:00). Fructose (F) or glucose (G) was supplied in the drinking water (10%) in order to prevent hypoglycemia. The rats were divided into 5 groups: (1) hyperinsulinemia with F water: group F+I; (2) hyperinsulinemia with G water: group G+I; (3) F water alone: group F; (4) G water alone: group G; and (5) control rats without sugar water group C. After 6 months of daily insulin injection triglyceride secretion rate (TGSR) was estimated using Triton WR1339 in all the rats. Groups F+I and G+I were obese and hypoglycemic compared to the other groups. Fasting plasma glucose level of group F was higher than any other group value. TGSR of group F+I was significantly higher than that of the control group, while that of group G+I was not, indicating that long-term hyperinsulinemia can stimulate hepatic triglyceride production when the rats were supplemented only with fructose. On the other hand, the rats in group G+I showed the lowest plasma free fatty acid level of all and their postheparin lipolytic activity was significantly elevated compared to that of the control rats. Moreover, they had suppressed plasma triglyceride levels and its fractional catabolic rate was significantly increased, suggesting that hyperinsulinemia can still stimulate triglyceride removal from the circulation of glucose supplemented rats even at month 6. In conclusion, exogenous hyperinsulinemia can stimulate hepatic triglyceride secretion even after 6 months duration when supplemented with fructose, while its stimulating effect on triglyceride removal from the circulation can be seen only with glucose supplementation. Thus, the effect of long-term hyperinsulinemia on plasma triglyceride turnover differs depending on the supplemented monosaccharides.

Down-regulation of tissue lipoprotein lipase expression in experimental chronic renal failure

Chronic renal failure (CRF) is associated with hypertriglyceridemia, impaired clearance of very low density lipoproteins (VLDL) and chylomicrons and their remnants as well as triglyceride-enrichment of various lipoproteins. These abnormalities are indicative of depressed lipoprotein lipase (LPL)-mediated hydrolysis of triglycerides in VLD and chylomicrons. In fact, impaired post-heparin lipolytic activity and decreased adipose tissue LPL activity has been previously demonstrated in CRF. The reduction in LPL activity in CRF has been attributed to PTH-induced insulin resistance and the presence of excess lipase inhibitors in uremic plasma. However, the effect of CRF on gene expression of LPL has not been elucidated and was studied here. Heparin-releasable, detergent-extractable and total LPL activities, as well as LPL mRNA of the heart, soleus muscle and fat body were determined in male Sprague-Dawley rats at baseline and on weeks 1, 3 and 6 following 5/6 nephrectomy (CRF group) or sham operation (control group). The CRF group exhibited a marked and steady rise in plasma triglycerides along with a steady decline in LPL activities and mRNA levels of all tissues studied. In contrast, the study parameters remained virtually unchanged throughout the study period in the control group. A strong inverse correlation was found between plasma triglycerides and LPL activity in the study animals. LPL activity was directly related to LPL mRNA. We conclude that CRF results in marked down-regulation of LPL expression that can contribute to dyslipidemia and altered energy metabolism in uremia. The effect of depressed LPL expression is compounded by the previously demonstrated elevations in uremic plasma of Apo C-III and pre-beta-HDL, which are potent inhibitors of LPL.

Defect in assembly process of very-low-density lipoprotein in suncus liver: an animal model of fatty liver.

We previously showed that fatty liver was easily induced in suncus by starvation and that the plasma level of apolipoprotein B (apo B) was very low. There are three possible explanations for the low level of apo B in the animals: low synthetic rate, low secretion rate, and rapid catabolism in the circulation of apo B. We measured post-heparin lipolytic activity (lipoprotein lipase activity), which plays a key role in the catabolism of apo B-containing lipoprotein, VLDL, and found no difference between rats and suncus. We also investigated the hepatic synthetic rate of apo B by liver perfusion studies. Newly synthesized apo B in the suncus liver was detected by immunoprecipitation and found to amount to 12.5% of that in rats. The secretion rate of VLDL in suncus, which was estimated by intravenous injection of Triton WR1339, was 13.8% of that in rats. These two results suggest that there is no major defect in the secretory process. We separated Golgi apparatus from rat and suncus livers, and found much fewer lipoprotein particles in suncus than in rat Golgi apparatus. This evidence suggests that there is no defect in the lipolytic process or hepatic secretory process of apo B-containing lipoprotein, VLDL, but there may be a defect in the assembly process of VLDL and/or in the synthetic process of apo B in suncus. Such a defect may be one of the reasons for starvation-induced fatty liver in suncus.

Effects of an American Heart Association step I diet and weight loss on lipoprotein lipid levels in obese men with silent myocardial ischemia and reduced high-density lipoprotein cholesterol

Reduced plasma concentrations of high-density lipoprotein cholesterol (HDL-C) are a risk factor for coronary artery disease (CAD). In this study, we examined the sequential effects of an isocaloric American Heart Association (AHA) step I diet and a hypocaloric AHA step I diet (AHA step I diet + weight loss) on lipoprotein lipid levels in 14 middle-aged and older (60 ± 6 years, mean ± SD) obese (body mass index [BMI] > 27 kg/m 2) nondiabetic men with exercise-induced silent myocardial ischemia (SI) and reduced HDL-C levels (0.85 ± 0.14 mmol/L). Nine men of comparable age and obesity and with no evidence of exercise-induced ischemia that were evaluated longitudinally served as metabolic controls. In men with SI, after 3 months on the isocaloric AHA step I diet plasma triglyceride (TG) levels decreased by 26% (2.25 ± 0.66 to 1.67 ± 0.69 mmol/L, P < .005), cholesterol by 12% (5.24 ± 0.84 to 4.62 ± 0.78 mmol/L, P < .01), and low-density lipoprotein cholesterol (LDL-C) by 10% (3.40 ± 0.69 to 3.05 ± 0.70 mmol/L, P < .01). However, plasma HDL-C levels also decreased by 7% (0.85 ± 0.14 to 0.79 ± 0.13 mmol/L, P < .05). Subsequent weight loss (11 ± 4 kg) in conjunction with the AHA step I diet resulted in an additional decrease of 24% in TG ( P < .005), 10% in cholesterol ( P < .05), and 10% in LDL-C ( P < .05). Plasma HDL-C levels increased by 8% ( P < .01), thereby correcting the decline seen on the AHA step I diet alone. Postheparin hepatic lipase (HL) activity decreased with weight loss ( P < .005), with no significant change in lipoprotein lipase (LPL) activity. There were no significant changes in lipoprotein lipids or postheparin lipolytic activity in the metabolic controls. Therefore, in men with SI, the sequential interventions of an isocaloric AHA step I diet and an AHA step I diet with weight loss decreased plasma TG levels by 44% ( P < .0001), LDL-C levels by 18% ( P < .0001), and the LDL-C to HDL-C ratio by 19% ( P < .005), with no significant change in HDL-C levels. Additional treatment modalities that include supervised exercise programs and drug therapy may be warranted in older obese subjects whose HDL-C levels do not normalize with diet and weight-loss interventions alone.

Lipoprotein lipase activity and plasma triglyceride clearance are elevated in endurance-trained women

Numerous studies have examined factors regulating high-density lipoprotein cholesterol (HDL-C) levels in male endurance athletes, but few studies have examined HDL-C regulation in female athletes. The present study compared lipid and lipoprotein concentrations, postheparin lipolytic activities, and the clearance rate ( K 2) of triglycerides following an intravenous fat infusion in 12 female distance runners (aged 33 ± 9 years, mean ± SD) and 13 sedentary women (33 ± 9 years). Runners were leaner and had greater maximum oxygen uptake values than controls. Runners also had nonsignificantly lower triglyceride (53 ± 15 v 65 ± 13 mg/dL) and higher HDL-C (62 ± 14 v 52 ± 8 mg/dL, P = .06). Lipoprotein lipase activity (LPLA) was 33% greater ( P < .05) and fat clearance ( K 2) was 27% faster ( P < .01) in the trained women, and LPLA correlated directly with K 2 ( r = .61) and HDL-C ( r = .62) in this group ( P < .05 for both). K 2 was directly related to HDL-C in the athletes ( r = .57, P = .06), and also when the active and sedentary women were combined ( r = .43, P < .05). These results suggest that increased LPLA and enhanced plasma triglyceride clearance may contribute to the HDL-C levels of physically active premenopausal women.

Role of lipoproteins in progressive renal disease.

Renal diseases are often associated with hyperlipoproteinemia and dyslipoproteinemia. Total serum cholesterol and triglycerides are increased in nephrotic syndrome regardless of etiology. Approximately 40 to 50% of patients with renal insufficiency requiring hemodialysis show hypertriglyceridemia and dyslipoproteinemia. During chronic hemodialysis, high doses of unfractionated heparin deplete post-heparin lipolytic activity and aggravate dyslipoproteinemia. Hypercholestrolemia and hyperlipoproteinemia are often encountered in patients taking glucocorticoids and cyclosporin A after renal transplantation. Observations in experimental animals and in patients with genetically determined and acquired hyperlipidemias suggest that lipids can damage the kidney and lead to glomerulosclerosis. In vitro cell-culture studies of human glomerular cells have been useful in providing information on lipid-induced glomerular damage. Thus, there are strong indications that lipoproteins may play a critical role in the development of mesangial cell damage and progressive renal disease. Therapeutic measures that reduce and correct dyslipoproteinemia in renal disease may have long-term beneficial effects on the amelioration of renal disease.

Circulating Tumor Necrosis Factor-α Levels and Lipid Abnormalities in Patients with Cystic Fibrosis

Hyperlipidemia is prominent among the disturbances in intermediary metabolism that occur subsequent to infections by microorganisms. The response to such infections is known to involve several cell types and is mediated by cytokines. We hypothesized that metabolic lipid disturbances seen during infection in cystic fibrosis (CF) patients may partly be the result of excessive tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine known to cause a large spectrum of pathophysiologic alterations, including impaired lipid metabolism. Therefore, we determined the circulating concentration of TNF-alpha and analyzed its relationship to lipid and lipoprotein levels, as well as lipoprotein lipase activity, in 31 CF patients. Plasma TNF-alpha values were significantly (p < 0.01) elevated in patients with CF compared with controls. The CF subjects were found to have decreased plasma cholesterol (25%), LDL cholesterol (35%), and HDL cholesterol (19%) concentrations, whereas plasma triglycerides were significantly increased (p < 0.001). The apo A-I level was reduced (p < 0.005), whereas apo B levels were normal. Low levels of the major essential fatty acids were found in the plasma of the CF patients, and the triene/tetraene ratio confirmed their essential fatty acid deficiency. Postheparin lipolytic activity was lower in CF patients than in controls, and the decreased activity was accounted for primarily by a decline in hepatic lipase. A significant positive correlation (p < 0.001, r = 0.70) was found between TNF-alpha and plasma triglyceride levels. However, no association was noted between TNF-alpha and essential fatty acid, cholesterol, or lipoprotein cholesterol levels, or with lipoprotein lipase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance.

To establish whether insulin resistance and/or postprandial fatty acid metabolism might contribute to familial combined hyperlipidemia (FCH) we have examined parameters of insulin resistance and lipid metabolism in six FCH kindreds. Probands and relatives (n = 56) were divided into three tertiles on the basis of fasting plasma triglycerides (TG). Individuals in the highest tertile (TG > 2.5 mM; n = 14) were older and had increased body mass index, systolic blood pressure, and fasting plasma insulin concentrations compared with individuals in the lowest tertile (n = 24). The former also presented with decreased HDL cholesterol and increased total plasma cholesterol, HDL-TG, and apoprotein B, E, and CIII concentrations. Insulin concentrations were positively correlated with plasma apo B, apo CIII, apo E, and TG, and inversely with HDL cholesterol. Fasting nonesterified fatty acids (NEFA) were elevated in FCH subjects compared to six unrelated controls and five subjects with familial hypertriglyceridemia. Prolonged and exaggerated postprandial plasma NEFA concentrations were found in five hypertriglyceridemic FCH probands. In FCH the X2 minor allele of the AI-CIII-AIV gene cluster was associated with increased fasting plasma TG, apo CIII, apo AI, and NEFA concentrations and decreased postheparin lipolytic activities. The clustering of risk factors associated with insulin resistance in FCH indicates a common metabolic basis for the FCH phenotype and the syndrome of insulin resistance probably mediated by an impaired fatty acid metabolism.

The effect of testosterone aromatization on high-density lipoprotein cholesterol level and postheparin lipolytic activity

Stanozolol, an oral 17α-alkylated androgen, increases hepatic triglyceride lipase activity (HTGLA) and decreases high-density lipoprotein cholesterol (HDL-C) levels, whereas intramuscular testosterone has comparatively little effect. In the present study, we tested the hypothesis that aromatization of androgen to estrogen blunts the lipid and lipase effects of exogenous testosterone. Fourteen male weightlifters received testosterone enanthate (200 mg/wk intramuscularly), the aromatase inhibitor testolactone (250 mg four times per day), or both drugs together in a randomized cross-over design. Serum testosterone level increased during all three drug treatments, whereas estradiol level increased only with testosterone alone (+47%, P < .05), demonstrating that testolactone effectively inhibited testosterone aromatization. Testosterone decreased HDL-C (−16%, P < .05), HDL 2-C (−23%, NS), and apoprotein (apo) A-I (−12%, P < .05) levels, effects that were consistently but not significantly greater with simultaneous testosterone and testolactone administration (HDL-C, −20%; HDL 2-C, −30%; apo A-I, −15%; P < .05 for all). In contrast, both testosterone regimens decreased HDL 3-C levels by 13% ( P < .05 for both). HTGLA increased 21% during testosterone treatment and 38% during combined testosterone and testolactone treatment ( P < .01 for both). Lipoprotein lipase activity (LPLA) increased only during combined testosterone and testolactone treatment (+31%, P < .01), suggesting that estrogen production may counteract the effects of testosterone on LPLA. Testolactone alone had little effect on any lipid, lipoprotein, apoprotein, or lipase concentration. We conclude that aromatization of exogenous testosterone to estradiol inhibits androgen-mediated elevations in HTGLA and reductions in HDL 2-C and apo A-I, but the effect is small and does not account for the markedly different lipid and lipase effects between oral androgens and intramuscular testosterone.

Continuous infusion of interleukin-1 beta in rats induces a profound fall in plasma levels of cholesterol and triglycerides.

During infectious diseases, striking alterations in plasma concentrations of cholesterol (hypocholesterolemia) and triglycerides (hypertriglyceridemia) may occur. It has been suggested that interleukin-1 is a mediator of these alterations. We studied the effects of continuous administration of recombinant human interleukin-1 beta (rhIL-1 beta) on plasma levels of cholesterol and triglycerides. A total of 42 rats were equipped with minipumps loaded with either rhIL-1 beta (delivery rate of 0.5, 2.0, or 4.0 micrograms/day i.p. for 1 week) or saline. After 1 day of treatment with rhIL-1 beta, plasma cholesterol levels had not changed. On day 2 a remarkable decrease of plasma cholesterol levels was observed in rats treated with 2.0 micrograms rhIL-1 beta/day (1.49 +/- 0.13 versus 2.23 +/- 0.08 mmol/l, p less than 0.005; rhIL-1 beta versus saline) or 4.0 micrograms rhIL-1 beta/day (1.46 +/- 0.04 versus 2.18 +/- 0.04 mmol/l,p less than 0.0005). This decrease persisted until the end of the experiment and occurred in all major lipoprotein fractions. Triglycerides in plasma (and in very low density lipoprotein) decreased almost concomitantly with plasma cholesterol, although to a lesser degree. Infusion of 2.0 micrograms rhIL-1 beta/day did not affect either cholesterol esterification or total postheparin lipolytic activity in plasma. Long-term infusion with 4.0 micrograms rhIL-1 beta/day induced prolonged fever, whereas at the lower doses temperatures were elevated only the first 2 days. rhIL-1 beta at a dose of 2.0 and 4.0 micrograms/day induced a transient decrease of food intake and a suppression of body weight gain.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of fasting plasma triglyceride levels: metabolism of hepatic and intestinal lipoproteins.

The contribution of the kinetics of exogeneous and endogenous lipoproteins in determining the level of triglyceride in fasting plasma was assessed in a group of 19 normolipidaemic and hypertriglyceridaemic subjects. From data derived during a 9-h infusion of [15N]-glycine, we have assessed very low density lipoprotein apolipoprotein B production, and from data analysed by kinetic modelling obtained following ingestion of retinol and triolein, we have assessed chylomicron and chylomicron remnant clearance in a group of 19 normolipidaemic and hypertriglyceridaemic subjects. A strong positive correlation was observed between the fasting plasma triglyceride level and the reciprocal of the apolipoprotein B fractional synthetic rate (r = 0.83, P less than 0.01). A positive correlation was also found with the rate of clearance of chylomicron remnants (Sf 20-400; r = 0.87, P less than 0.01) and of chylomicrons (Sf greater than 400; r = 0.69, P less than 0.01). No correlation was found between the fasting plasma triglyceride level and either of the plasma post-heparin lipolytic activities. Multivariate analysis revealed that 95% of the variance in triglyceride levels could be explained by the apolipoprotein B fractional synthetic rate and the chylomicron remnant clearance rate. The strong correlation between chylomicron remnant clearance, a measure of exogenous lipid metabolism, and fasting (hence, endogenous) plasma triglyceride levels suggests that remnants of chylomicrons and very low density lipoproteins share some common components of the removal process.

Preheparin lipoprotein lipolytic activities: relationship to plasma lipoproteins and postheparin lipolytic activities.

To determine the putative metabolic relevance of preheparin versus postheparin lipoprotein lipases, the relationships of both pre- and postheparin lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) to plasma triglycerides, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) cholesterol were determined in 93 men. Relationships of preheparin lipases to their respective postheparin lipases were also examined. Although relationships between the preheparin lipases and plasma triglycerides and HDL cholesterol were not apparent, both preheparin LPL (rs = 0.306, P = 0.0036) and HTGL (rs = 0.348, P = 0.0008) correlated with LDL cholesterol, a relationship not seen with either postheparin lipase. Both postheparin LPL (rs = 0.515, P = 0.0001) and postheparin HTGL (rs = -0.228, P = 0.0028), however, correlated with HDL cholesterol. In addition, postheparin LPL was inversely correlated with postheparin HTGL (rs = -0.363, P = 0.0003), whereas the relationship between preheparin LPL and preheparin HTGL was positive (rs = 0.228, P = 0.0009). Overall, these data point to differences between pre- and postheparin lipases in their relationships to lipoproteins, and one to another. The relationships of LDL cholesterol to both preheparin LPL and HTGL suggest that displacement of active forms of both lipases from their endothelial binding sites may mark triglyceride-rich lipoproteins or their remnants for metabolic pathways that lead to LDL.

Effect of acute intravenous alcohol on plasma lipoprotein in man

The effect of acute administration of ethanol was determined on plasma lipoproteins and post-heparin lipolytic activities in six normal subjects. Ethanol was administered intravenously (IV) in a dose of 0.6 g/kg body weight over 1 hour and blood samples were obtained for 4 hours thereafter. In four subjects, the determinations were repeated after the infusion of an isovolumetric amount of saline. Ethanol resulted in a rapid increase in plasma triglycerides, which persisted throughout the study. Ethanol did not result in changes in high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, or apolipoprotein (apo) A-1. However, ethanol decreased apo B and delayed increases in lipolytic activities from 15 to 30 minutes after the administration of heparin. The increase in triglycerides without changes in HDL-cholesterol after acute ethanol administration may contribute to an increased severity of cardiovascular disease in binge drinkers.