Low Lipoprotein Lipase Research Articles

Low lipoprotein lipase mass in preheparin serum of type 2 diabetes mellitus patients and its recovery with insulin therapy

There exists lipoprotein lipase mass in preheparin serum, even though the activity is scarcely found. We studied the preheparin serum lipoprotein lipase mass levels (prehaparin LPL mass) in type 2 diabetes mellitus patients and the effect of insulin therapy on the levels of preheparin LPL mass. In 40 type 2 diabetes mellitus patients, preheparin LPL mass were measured by the sandwich enzyme-linked immunosorbent assay (ELISA), and were compared with those of non-diabetic healthy control. The correlation between preheparin LPL mass and Hemoglobin A 1c (HbA 1c), serum lipids were studied. Preheparin LPL mass were measured before and after insulin therapy. Preheparin LPL mass of type 2 diabetes mellitus patients was significantly lower than that of non-diabetic healthy control. In diabetic patients, preheparin LPL mass were negatively correlated with HbA 1c. Fifteen patients started to take insulin therapy. Preheparin LPL mass increased significanaly at 4th week, when fasting blood glucose decreased. These results suggested that preheparin LPL mass was greatly regulated by insulin action.

Association of Backfat Thickness with Postheparin Lipoprotein Lipase Activity and Very Low Density Lipoprotein-Subfractions in Growing Pigs

Sixteen pigs from 2 distinct genetic lines (LGAH and VFIL) obtained after eight generations of divergent selection for high (H) and low (L) lean tissue growth rate with ad-libitum feeding (LGA) and voluntary feed intake (VFI), respectively, were used in this study. The objectives of this investigation were to establish appropriate working conditions for the postheparin plasma lipoprotein lipase (LPL) assay and to study relationships between fat deposition and plasma lipids, very low density lipoprotein (VLDL) lipids, VLDL-subfractions and postheparin plasma LPL activity in growing pigs. Four preliminary experiments were performed to determine the appropriate working conditions for the postheparin plasma LPL assays. Postheparin plasma preincubated with SDS (20-50 mM) at 26°C for 45 minutes inhibited hepatic lipase activity. A total of 2 μl VLDL/assay produced maximum stimulation of LPL activity. Postheparin plasma protein and increasing incubation time contributed an optimum response. LGAH pigs had a significantly higher proportion subfraction 2 than VFIL pigs. No differences were observed in postheparin plasma LPL activity and backfat thickness for two lines of pigs. There were positive correlations between backfat thickness and proportion of subfractions 2 and postheparin plasma LPL activity but the results were not statistically significant. Backfat thickness was not statistically correlated with proportion of subfraction 2 and postheparin plasma LPL activity in a multiple regression analysis. It is believed that the apolipoprotein E, which is present in higher quantities in VLDL-subfraction 2 plays an important role for clearing VLDL triacylglycerol into adipose tissue. LPL activity of pigs can be measured by using postheparin plasma technique. If the relationships of backfat thickness and VLDL-subfraction 2 and postheparin plasma LPL activity can be established, it suggests that these parameters could be used as indicators in selection programmes. Further experiments need to be conducted by using larger sample size and different breed of pigs with greater differences in backfat thicknesses to confirm these trends.

Weaning affects lipoprotein lipase activity and gene expression in adipose tissues and in masseter but not in other muscles of the calf.

The nutritional and physiological modifications that occur during the weaning period induce adaptations of tissue metabolism in all mammal species. Among the adaptations due to weaning in ruminants, the regulation of lipoprotein lipase (LPL) activity, one of the rate-limiting steps of fatty acid utilization by tissues, was still unknown. The present study aimed at comparing LPL activity and gene expression in the heart, seven skeletal muscles and three adipose tissue sites between two groups of seven preruminant (PR) or ruminant (R) calves having a similar age (170 d), similar empty body weight (194 kg) at slaughter, and similar net energy intake from birth onwards. Triacylglycerol content of adipose tissues was 16 % lower in R than in PR calves, This could be partly the result from a lower LPL activity (-57 %, ). LPL mRNA levels were also lower in R calves (-48 % to -68 %, ) suggesting a pretranslational regulation of LPL activity. Activity and mRNA levels of LPL did not differ significantly in the heart and skeletal muscles except in the masseter in which LPL activity and mRNA levels were higher (+50 % and +120 % respectively, ) in the R calves. Regulation of LPL in masseter could be explained by the high contractile activity of this muscle after weaning due to solid food chewing. In conclusion, weaning in the calf affects LPL activity and expression in adipose tissues, but not in skeletal muscles except the masseter.

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.

In vivo evidence for the role of lipoprotein lipase activity in the regulation of apolipoprotein AI metabolism: a kinetic study in control subjects and patients with type II diabetes mellitus.

The aim of this study was to delineate the role of lipoprotein lipase (LPL) activity in the kinetic alterations of high density lipoprotein (HDL) metabolism in patients with type II diabetes mellitus compared with controls. The kinetics of HDL were studied by endogenous labeling of HDL apolipoprotein AI (HDL-apo AI) using a primed infusion of D(3)-leucine. The HDL-apo AI fractional catabolic rate (FCR) was significantly increased (0.32 +/- 0.07 vs. 0.23 +/- 0.05 pool/day; P < 0.01), and HDL composition was changed [HDL cholesterol, 0.77 +/- 0.16 vs. 1.19 +/- 0.37 mmol/L (P < 0.05); HDL triglycerides, 0.19 +/- 0.12 vs. 0.10 +/- 0.03 mmol/L (P < 0.05)] in diabetic patients compared with healthy subjects. HDL-apo AI FCR was correlated to plasma and HDL triglyceride concentrations (r = 0.82; P < 0.05 and r = 0.80; P < 0.05, respectively) and to homeostasis model assessment (r = 0.78; P < 0.05). Postheparin plasma LPL activity was decreased in type II diabetes (6.8 +/- 2.8 vs. 18.1 +/- 5.2 micromol/mL postheparin plasma.h; P < 0.005) compared with that in healthy subjects and was correlated to the FCR of HDL-apo AI (r = -0.63; P < 0.05). LPL activity was also correlated with HDL cholesterol (r = 0.78; P < 0.05), plasma and HDL triglycerides (r = -0.87; P < 0.005 and r = -0.83; P < 0.05, respectively), and homeostasis model assessment (r = -0.79; P < 0.05). In addition, the LPL to hepatic lipase ratio was correlated with the catabolic rate of HDL (r = -0.76; P < 0.06). These results suggest that a decrease in the LPL to hepatic lipase ratio in type II diabetes mellitus, mainly related to lowered LPL activity, could induce an increase in HDL catabolism. These alterations in HDL kinetics in type II diabetes proceed to some extent from changes in their composition, probably linked to an increase in triglyceride transfer from very low density lipoprotein particles, in close relationship with LPL activity and resistance to insulin.

Different origin of hypertriglyceridemia induced by a high-fat and a high-sucrose diet in ventromedial hypothalamic-lesioned obese and normal rats.

To clarify the mechanism by which plasma triacylglycerol is affected by a high fat or a sucrose diet. Two sets of six groups each having six rats were prepared-(1) ventromedial hypothalamic (VMH)-lesioned rats fed a standard diet; (2) sham VMH-lesioned rats fed a standard diet; (3) VMH-lesioned rats fed a high-fat diet; (4) sham VMH-lesioned rats fed a high-fat diet; (5) VMH-lesioned rats fed a high-sucrose diet; and (6) sham VMH-lesioned rats fed a high-sucrose diet. After VMH lesions and sham operations, the rats were provided standard, high-fat and high sucrose diets for 2 weeks. Two weeks later, blood samples were collected after overnight fast to determine plasma triacylglycerol (TAG), hepatic triacylglycerol secretion rate (TGSR), fractional catabolic rate (FCR) of triacylglycerol and postheparin plasma lipoprotein lipase (LPL), plasma glucose, insulin and leptin. Values of TAG, TGSR, FCR and LPL in VMH-lesioned obese rats were all greater than those in sham-operated rats, regardless of the diet fed. In sham-operated rats, high-fat diet fed rats showed higher TAG with similar TGSR, higher LPL and lower FCR than those of standard diet fed rats. High-sucrose diet fed rats showed significantly higher TAG with higher TGSR, higher LPL and lower FCR than those of standard diet fed rats. Moreover, high-sucrose diet fed rats showed higher TAG with higher TGSR, lower LPL and higher FCR than those of high-fat diet fed rats. In VMH-lesioned rats, high-fat diet fed rats showed higher TAG with similar TGSR, higher LPL and lower FCR than those of standard diet fed rats. High-sucrose diet fed rats showed markedly higher TAG with notably higher TGSR, higher LPL and lower FCR than those of standard diet fed rats. High-sucrose diet fed rats showed still higher TAG with markedly higher TGSR, similar LPL and higher FCR than those of high-fat diet fed rats. The mechanism by which TAG metabolism is affected by a high-fat or a high-sucrose diet differed; a high-fat diet increased plasma TAG level by lowering removal of TAG without increase in hepatic TAG secretion in sham-operated (normal) rats. A high-sucrose diet, in contrast, induced much higher plasma TAG levels by both increased hepatic TAG secretion and decreased removal of TAG. The effects of a high-fat or a high-sucrose diet were similar but exaggerated in VMH lesioned animals.

Hypoalbuminemia and proteinuria contribute separately to reduced lipoprotein catabolism in the nephrotic syndrome

Hypertriglyceridemia is a result of reduced triglyceride (TG)-rich lipoprotein (TRL) catabolism and occurs in rats with nephrotic syndrome (NS) and in Nagase analbuminemic rats (NARs). While the heparin-releasable lipoprotein lipase (LpL) pool in NAR and in NS is similar, TG levels are significantly greater in NS, suggesting that factors other than reduced LpL alone act in NS but not in NARs. Furthermore, clearance of chylomicrons (CM) and very low-density lipoprotein (VLDL) is normal in vivo in NAR despite low LpL levels. We tested the hypotheses that impaired binding of VLDL and impaired VLDL-high density lipoprotein (HDL) interactions contribute to hyperlipidemia in NS. TG and apoB secretion was measured using Triton WR 1339. Clearance of CMs by perfused hearts from NS and NAR was determined. Binding of VLDL from control, NS and NAR to rat aortic endothelial cells (RAECs) was measured prior to and following incubation with HDL from NS, NARs, and control. ApoE, protein, and TG content was determined. TG levels were greatest in NS (516 +/- 95 mg/dL), intermediate in NAR (193 +/- 20), and least in control (97 +/- 16, P = 0.05), while in contrast, TG secretion was least in NS (178 +/- 33 mg/dL/hour) versus 212 +/- 17 in NAR and 294 +/- 15 in control (P < 0.001 vs. NS). Clearance of CMs by NS and NAR hearts was the same and significantly reduced versus control (P < 0.005). Binding of NS-VLDL to endothelial cells was reduced, while NAR-VLDL binding was increased versus control (P < 0.001). Incubation of NS-VLDL with control or NAR HDL increased VLDL binding compared with binding following incubation with NS HDL (P < 0.001). Increased TG levels in both NS and NAR are the result of decreased TRL clearance. TG levels are greater in NS because of the presence of a combined defect: (1) a decrease in endothelial-bound LpL that occurs as a consequence of reduced serum albumin concentration, and (2) a defect in VLDL binding to endothelial-bound LpL. This latter defect occurs only in the presence of proteinuria and is conferred by HDL.

Preheparin serum lipoprotein lipase mass is negatively related to coronary atherosclerosis

In preheparin serum, there exists lipoprotein lipase (LPL) mass with little activity. The clinical significance of this preheparin serum LPL mass (preheparin LPL mass) is unclear. We studied the levels of preheparin LPL mass in patients with coronary atherosclerosis, comparing the results with those in healthy men. We also evaluated the correlation between preheparin LPL mass and the severity of coronary atherosclerosis by comparing with other risk factors such as age, smoking, family history, hypertension, hyperuricemia, diabetes mellitus, total cholesterol, triglyceride, high density lipoprotein-cholesterol and body mass index. The subjects, 70 men presenting with symptoms of coronary artery disease, underwent coronary angiographic examination. Significant narrowness was defined as≥75%. Control group comprised 77 men who had annual health checks and showed no abnormal findings. Preheparin LPL mass in the stenosis group was lower than normal coronary group and also than the control group. Multivariate analysis showed that preheparin LPL mass had the highest t-value (−2.53) for the number of lesions among the risk factors listed above. These results suggest that low preheparin LPL mass may be deeply involved in the progression of coronary atherosclerosis.

Metabolism in two breeds of geese with moderate or large overfeeding induced liver-steatosis

Biochemical mechanisms which may control fat deposition in liver and/or peripheral tissues have been studied in Poland and Landes geese. Post-prandial plasma substrates and post-heparin lipoprotein-lipase (LPL) activity were measured in 10-week-old animals. At 23 weeks of age, geese were overfed for 14 days then slaughtered. Hepatic steatosis was more important in Landes geese, while muscle and subcutaneous adipose tissue were less developed. In this breed, fatty liver weight negatively scaled to LPL activity, suggesting that a low LPL activity is a limiting factor of peripheral fat deposition. Consequently, non-catabolized VLDL may return to liver and increase hepatic steatosis. In Poland geese, such a mechanism does not exist. On the other hand, fatty liver weight was positively correlated to very low density lipoproteins (VLDL) and triacylglycerols measured in overfed Poland geese, suggesting that lipids synthetized by liver are better transfered from liver to extrahepatic tissues. Kinetics of post-prandial plasma glucose, triacylglycerols, phospholipids and uric acid were similar in the two breeds. However, the marked decrease in post-prandial plasma glycerol in Poland geese suggests that an extrahepatic tissue lipolysis inhibition could contribute to the higher peripheral fattening in overfed Poland geese and could be a limiting factor of hepatic steatosis in this breed.

Contribution of hyperinsulinemia to modulation of lipoprotein lipase activity on the obese Zucker rat

This study was designed to assess the contribution of hyperinsulinemia to the maintenance of high adipose and low muscle lipoprotein lipase (LPL) activity in the obese Zucker fa/fa rat. Insulinemia in obese Zucker rats was reduced for 4 days with a single injection of low-dose streptozotocin (STZ). Saline-injected intact obese (obese-INT) and STZ-injected obese (obese-STZ) rats were compared with a lean Fa/? reference group. LPL activity was assessed after a 12-hour fast, with or without a 1-hour refeeding period. Fasting serum insulin levels were 17-fold higher in obese-INT versus lean rats and were reduced to 60% of obese-INT levels in obese-STZ animals. In the postprandial state, serum insulin levels remained low in obese-STZ rats and were similar to the values in lean animals, whereas insulinemia increased in the obese-INT group to 18-fold the levels in lean rats. Serum glucose, nonesterified fatty acid (NEFA), and triglyceride levels, which were higher in obese-INT versus lean rats, were further increased in the obese-STZ group. Tissue weights of obese rats were unaffected by STZ treatment. Fasting LPL specific activity was higher in white adipose tissue ([WAT] +87%) and brown adipose tissue ([BAT] +167%) of obese-INT versus lean rats. Reducing the insulinemia in obese-STZ rats reduced fasting enzyme activity to the levels in lean animals in both WAT and BAT. Insulinemia and adipose LPL activity were positively correlated in the fasted state. Acute food intake increased WAT LPL activity in lean animals, but not in obese animals. Soleus LPL activity was lower in obese-INT compared with lean rats and was further decreased in obese-STZ animals. Heart LPL was decreased only in obese-STZ rats compared with the lean group. LPL in muscle tissue was not correlated with insulinemia, but an inverse relationship was found between serum NEFA levels and enzyme activity. It is concluded that in the obese Zucker rat, hyperinsulinemia is responsible for the maintenance of elevated basal LPL activity in adipose tissue independently of fat mass, whereas muscle enzyme activity appears to be more strongly and inversely related to the availability or tissue utilization of lipid substrates.

Seasonal thermogenic acclimation of diurnally and nocturnally active desert spiny mice.

Diurnally active golden spiny mice (Acomys russatus) and nocturnal common spiny mice (Acomys cahirinus) coexist in hot rocky deserts of Israel. Diurnal and nocturnal activities expose these species to different climatic conditions. Nonshivering thermogenesis (NST) capacity of individuals of both species immediately upon removal from the field exhibited seasonal changes, with no significant interspecific difference. Colony-reared mice of either species transferred in the laboratory from long to short photoperiod increased NST capacity, though to a lesser extent than observed in the seasonal acclimatization. The underlying biochemical mechanisms of short photoperiod acclimation differed between the species. In both Cytochrome-c oxidase (Cox) activity was higher in short as compared to long photoperiod. In short-photoperiod-acclimated A. cahirinus uncoupling protein (UCP) content in brown adipose tissue (BAT) was significantly higher than in long photoperiod, while in A. russatus there was no significant change. In A. russatus there was a significant increase in lipoprotein lipase (LPL) activity in BAT in short-photoperiod-acclimated individuals, while in A. cahirinus LPL activity was high under both acclimations. The low LPL activity in brown adipose tissue of desert-adapted A. russatus may facilitate lipid uptake in white adipose tissue, an advantage in desert conditions where food is scarce and irregularly distributed in space and time.

Lipoprotein abnormalities in diabetic nephropathy

The risk of death from coronary heart disease (CHD) is substantially increased in diabetic nephropathy compared with normal subjects or diabetes without nephropathy. I tried to define abnormal plasma lipoproteins profiles contributing to the increased CHD risk in diabetic nephropathy. This study included: middle-aged to older type 2 diabetic patients with normoalbuminuria, microalbuminuria, and overt albuminuria; nondiabetic patients with primary renal disease; and normal control subjects. Triglyceride (TG) levels were significantly increased in type 2 diabetic patients with microalbuminuria and overt proteinuria. Glycemic control or insulin resistance were not associated with TG levels. Intermediate-density lipoprotein (IDL) and remnant-like particle (RLP) cholesterol in type 2 diabetics were significantly elevated in patients with overt nephropathy. Hepatic TG lipase (HTGL) was significantly decreased in diabetic nephropathy, and their higher IDL levels were inversely related to decreased HTGL. Low-density lipoprotein (LDL) size was significantly smaller in diabetic nephropathy compared with nondiabetics with kidney disease. The TG response after the oral fat load was significantly greater in diabetic nephropathy, and the LDL size was inversely associated with the magnitude of postprandial lipemia. Microalbuminuric diabetic patients had a lower lipoprotein lipase (LPL) mass and a higher von Willebrand factor (vWF), an indicator of endothelial cell damage, than normoalbuminuric patients. The LPL mass was inversely associated with vWF, suggesting that widespread endothelial cell damage results in a reduction in LPL bound to endothelium in diabetic subjects with microalbuminuria. Plasma lipoprotein profiles become more atherogenic in patients with diabetic nephropathy, including the subclinical stage, compared with diabetics without nephropathy or those with nondiabetic kidney disease.

Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins

Lipoprotein lipase (LPL) is crucial in the hydrolysis of triglycerides (TG) in TG-rich lipoproteins in the formation of HDL particles. As both these lipoproteins play an important role in the pathogenesis of atherosclerotic vascular disease, we sought to assess the relationship between post-heparin LPL (PH-LPL) activity and lipids and lipoproteins in a large, well-defined cohort of Dutch males with coronary artery disease (CAD). These subjects were drawn from the REGRESS study, totaled 730 in number and were evaluated against 75 healthy, normolipidemic male controls. Fasting mean PH-LPL activity in the CAD subjects was 108 (46) mU/ml, compared to 138 (44) mU/ml in controls (P < 0.0001). When these patients were divided into activity quartiles, those in the lowest versus the highest quartile had higher levels of TG (P < 0.001), VLDLc and VLDL-TG (P = 0.001). Conversely, levels of TC, LDL, and HDLc were lower in these patients (P = 0.001, P = 0.02, and P = 0.001, respectively). Also, in this cohort PH-LPL relationships with lipids and lipoproteins were not altered by apoE genotypes. The frequency of common mutations in the LPL gene associated with partial LPL deficiency (N291S and D9N carriers) in the lowest quartile for LPL activity was more than double the frequency in the highest quartile (12.0% vs. 5.0%; P = 0.006). By contrast, the frequency of the S447X LPL variant rose from 11.5% in the lowest to 18.3% (P = 0.006) in the highest quartile. This study, in a large cohort of CAD patients, has shown that PH-LPL activity is decreased (22%; P = 0.001) when compared to controls; that the D9N and N291S, and S447X LPL variants are genetic determinants, respectively, in CAD patients of low and high LPL PH-LPL activities; and that PH-LPL activity is strongly associated with changes in lipids and lipoproteins.—Henderson, H. E., J. J. P. Kastelein, A. H. Zwinderman, E. Gagne, J. W. Jukema, P. W. A. Reymer, B. E. Groenemeyer, K. I. Lie, A. V. G. Bruschke, M. R. Hayden, and H. Jansen. Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins. J. Lipid Res. 1999. 40: 735–743.

The Activity of HMG-CoA Reductase and Acetyl-CoA Carboxylase in Human Apocrine Sweat Glands, Sebaceous Glands, and Hair Follicles Is Regulated by Phosphorylation and by Exogenous Cholesterol

Human apocrine and sebaceous glands function to secrete lipids, predominantly triglycerides, fatty acids, cholesterol and its esters, and, in the sebaceous gland, squalene. The enzymes that catalyze the important regulatory steps in cholesterol and fatty acid biosyntheses, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and acetyl-CoA carboxylase, respectively, were therefore studied in isolated human skin appendages, and their relevant kinetic parameters determined. The enzyme activities that were observed can account for previously described rates of incorporation of radiolabeled substrates into the appropriate lipids by glands in vitro. Reduced enzyme activities following homogenization in the presence of fluoride indicated that both of these enzymes in skin appendages are inactivated by phosphorylation. The activity of the enzyme known to catalyze this phosphorylation, the AMP-activated protein kinase, was also measured. Compactin was shown to inhibit HMG-CoA reductase in homogenates of these appendages. Conversely, incubation of whole sebaceous glands with compactin resulted in the stimulation of enzyme activity, which suggests that these appendages can respond to diminishing cholesterol levels. The effect of exogenous low density lipoprotein and 25-hydroxycholesterol on HMG-CoA reductase activity from skin appendages was investigated. HMG-CoA reductase activity in both apocrine and sebaceous glands was reduced following incubation with either low density lipoprotein or 25-hydroxycholesterol. Low density lipoprotein receptor and lipoprotein lipase mRNA expression was also detected in skin appendages. These results indicate that apocrine and sebaceous glands have the capacity to sequester dietary cholesterol and fatty acids that may have important implications for the understanding of both acne and axillary odor.

Effect of the calcium channel antagonist nitrendipine on lipoprotein lipase and hepatic lipase in the normal rat

Several observations indicate that a low lipoprotein lipase (LPL)/hepatic lipase (HL) ratio clusters with clinical and laboratory features of atherosclerosis. Antihypertensive treatment can unfavourably interfere with lipid metabolism, counteracting the beneficial effects of lowering blood pressure. We have evaluated the effects of the Ca 2+ channel antagonist nitrendipine on tissue LPL and HL in the normal rat. At the dose of 40 mg/day administered intragastrically, a 5-day nitrendipine treatment induced a significant decrease in HL activity in the liver, in comparison to control animals: 656±82 mU/g tissue vs. 814±38 mU/g 3 h after the last administration; 640±70 mU/g vs. 893±101 mU/g 8 h after administration. LPL activity in heart was increased by active treatment: 2542±298 vs. 2115±244 mU/g in controls 3 h after administration, P<0.05. At variance, LPL mass, measured 8 h after administration, was decreased in heart of treated rats: 2.38±0.4 μg/g tissue vs. 3.88±0.3 μg/g in controls. The ratio between heparin-releasable and residual LPL in heart was unaffected by the drug. No changes were observed in LPL activity and mass in soleus muscle or in periepididymal adipose tissue. Our results indicate that nitrendipine, at the dose used, induces changes in lipolytic enzymes of rat tissues that could be beneficial in relation to atherosclerosis. These data encourage further investigations in humans, at the usual therapeutical doses.

Combined lipase deficiency ( cld/cld) in mice affects differently post-translational processing of lipoprotein lipase, hepatic lipase and pancreatic lipase

Lipoprotein lipase (LPL) and hepatic lipase (HL), which act on plasma lipoproteins, belong to the same gene family as pancreatic lipase. LPL is synthesized in heart, muscle and adipose tissue, while HL is synthesized primarily in liver. LPL is also synthesized in liver of newborn rodents. The active form of LPL is a dimer, whereas that of HL has not been established. Combined lipase deficiency (CLD) is an autosomal recessive mutation ( cld) in mice which impairs post-translational processing of LPL and HL. Cld/cld mice have very low LPL and HL activities (<5% of normal), yet normal pancreatic lipase activity. They develop massive hypertriglyceridemia and die within 3 days after birth. The CLD mutation allows synthesis, glycosylation and dimerization of LPL, but blocks activation and secretion of the lipase. Thus, dimerization per se does not result in production of active LPL. Immunofluoresence studies showed that LPL is retained in endoplasmic reticulum (ER) in cld/cld cells. Translocation of Golgi components to ER by treatment with brefeldin A (BRA) enabled synthesis of active LPL in cultured cld/cld brown adipocytes. Thus, production of inactive LPL in cld/cld cells results from inability of the cells to transport LPL from ER. The CLD mutation allows synthesis and glycosylation of HL, but blocks activation of the lipase. Immunofluoresence studies located HL mostly outside of cells in liver, liver cell cultures and incubated adrenal tissue of normal and cld/cld mice and mostly inside of cells in liver cell cultures and adrenal tissues treated with monensin (to block secretion of protein). These findings demonstrate synthesis and secretion of HL by both liver and adrenal cells of normal and cld/cld mice. Thus, the CLD mutation allows secretion of inactive HL by liver and adrenals. However, it does not block synthesis or secretion of active pancreatic lipase. Our findings indicate that LPL, HL and pancreatic lipase, although closely related, are processed differently.

Expression of type III hyperlipoproteinemia in patients homozygous for apolipoprotein E-2 is modulated by lipoprotein lipase and postprandial hyperinsulinemia.

Type III hyperlipoproteinemia (HLP) is a multifactorial disorder associated with homozygosity for the apolipoprotein (apo) E-2 allele. Factors which may promote the development of HLP include lipoprotein lipase (LPL) and hyperinsulinemia. These factors were investigated in eight patients with type III HLP and in nine normolipidemic controls. In vitro the interaction of apoE with LPL was analyzed in cell binding assays. All type III HLP patients showed delayed triglyceride (TG) clearance and remnant lipoprotein accumulation in an oral fat tolerance test. Normolipidemic apoE-2/2 controls revealed normal TG clearance comparable to apoE3/3 controls. HLP patients showed lower LPL activity and mass than controls. Analysis of the LPL gene revealed an Asn 291-->Ser mutation in three patients and a -93 T-G substitution combined with an Asp 9-->Asn mutation in one control subject. In addition to LPL abnormalities, postprandial hyperinsulinemia was observed in five out of eight patients. In vitro LPL compensated the defective function of apoE-2 in mediating remnant lipoprotein binding to cells. In summary, seven out of eight patients with type III HLP showed LPL abnormalities and/or postprandial hyperinsulinemia. Together with the in vitro data these findings support a coordinate effect of apoE and LPL for the manifestation of type III HLP. Hyperinsulinemia appears to be an additional factor important for disease expression.

Streptozotocin-induced diabetes enhances cardiac heparin-releasable lipoprotein lipase activity in spontaneously hypertensive rats.

Vascular endothelial-bound lipoprotein lipase (LPL), also known as heparin-releasable LPL, catalyzes the breakdown of the triglyceride component of lipoproteins and is rate-limiting for free fatty acid transport to tissues. We previously demonstrated that heparin-releasable LPL activity increases in diabetic Wistar rat hearts, whereas with the development of hypertension in spontaneously hypertensive rats (SHR), there is a concomitant and progressive reduction in LPL activity. The objective of the present study was to examine the regulation of cardiac LPL activity in SHR-diabetic rats. Heparin perfusion of the isolated Langendorff heart induced the release of LPL activity. SHR hearts demonstrated a reduction in peak heparin-releasable LPL activity, relative to Wistar controls. However, induction of streptozotocin-induced diabetes in SHR, as in Wistar rats, increased peak heparin-releasable LPL activity in perfused hearts. The elevated heparin-releasable LPL peak could not be accounted for by enhanced LPL synthesis in that both cellular and surface-bound LPL activities in myocytes from SHR-diabetic rats were low relative to control. Chronic (12-day) insulin treatment of SHR-diabetic rats reduced the augmented heparin-releasable LPL activity and increased cell-associated LPL activity. Moreover, acute (90-minute) treatment of SHR-diabetic rats with rapid-acting insulin also reduced the heparin-releasable LPL activity to normal, although it had no effect on the low cellular LPL activity. These results demonstrate that the diabetes-induced augmentation of cardiac LPL counteracts the reduction in enzyme activity associated with hypertension. This may serve to increase the delivery of free fatty acid to the heart, and the resultant metabolic changes may lead to the severe cardiomyopathy observed in the hypertensive-diabetic rat heart.

1.P.42 Small, dense LDL is associated with low lipoprotein lipase and high hepatic lipase activities, and alterations in IDL and VLDL composition

1.P.42 Small, dense LDL is associated with low lipoprotein lipase and high hepatic lipase activities, and alterations in IDL and VLDL composition

1.P.123 Hyperchylomicronemia syndrome due to low lipoprotein lipase activity associated with chronic idiopathic urticaria

1.P.123 Hyperchylomicronemia syndrome due to low lipoprotein lipase activity associated with chronic idiopathic urticaria