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Background: Lipoprotein lipase (LPL) expressed in macrophages plays an important role in promoting the development of atherosclerosis or atherogenesis. MicroRNA-182 (miR-182) is involved in the regulation of lipid metabolism and inflammation. However, it remains unclear how miR-182 regulates LPL and atherogenesis., Methods and results: Using bioinformatics analyses and a dual-luciferase reporter assay, we identified histone deacetylase 9 (HDAC9) as a target gene of miR-182. Moreover, miR-182 upregulated LPL expression by directly targetingHDAC9in THP-1 macrophages. Hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that apolipoprotein E (ApoE)-knockout (KO) mice treated with miR-182 exhibited more severe atherosclerotic plaques. Treatment with miR-182 increased CD68 and LPL expression in atherosclerotic lesions in ApoE-KO mice, as indicated by double immunofluorescence staining in the aortic sinus. Increased miR-182-induced increases in LPL expression in ApoE-KO mice was confirmed by real-time quantitative polymerase chain reaction and western blotting analyses. Treatment with miR-182 also increased plasma concentrations of proinflammatory cytokines and lipids in ApoE-KO mice., Conclusions: The results of the present study suggest that miR-182 upregulates LPL expression, promotes lipid accumulation in atherosclerotic lesions, and increases proinflammatory cytokine secretion, likely through targetingHDAC9, leading to an acceleration of atherogenesis in ApoE-KO mice.

Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility.

Background/aims: To delineate the hypotriglyceridemic effect of conjugated linoleic acid (CLA) in mice, the effect of this fatty acid on lipoprotein lipase (LPL) and apolipoprotein C-III (ApoCIII) mRNA accumulation in muscle, adipose and liver tissue was studied., Methods: CD-1 mice were housed in groups of 6 and randomized to one of three experimental diets for 3 weeks: SUC: 65% sucrose by weight; CLA: 1% CLA oil (34.4% c9,t11; 35.1% t10,c12 and 4.1% other conjugated isomers) and 65% sucrose, and DEX: 65% dextrose, as a control., Results: LPL mRNA levels in muscle tissue were increased in the DEX group and in the CLA group (240% increase) compared with the SUC group. In contrast, LPL mRNA levels were 81% lower in epididymal adipose tissue from the CLA group compared with the SUC group. There was no effect of dietary treatments on ApoCIII mRNA accumulation in the liver., Conclusions: These data suggest that dietary CLA may induce partitioning of circulating triglycerides to muscle tissue, preventing their accumulation in adipocytes., (2009 S. Karger AG, Basel.)

Lipoprotein lipase (LPL) deficiency is an extremely rare congenital metabolic disorder with an accumulation of chylomicrons in the blood. We encountered a patient with an LPL deficiency leading to multiple bone xanthomas associated with hyperlipidemia. Radiographs and MRI of the humerus and femur revealed symmetrical bone lesions, and there is a possibility that these symmetrical lesions may therefore be a characteristic feature for this disorder.

Polysaccharides from Auricularia auricula (AAP) extracted in hot water and precipitated by ethanol were chemically well defined, including 42.5% total carbohydrate, 19.6% uronic acids, 15.8% sulfate groups, 1.7% N, and 20.3% ash. Gas chromatography analysis demonstrated that the neutral sugars were mainly composed of rhamnose, xylose, and glucose and smaller amounts of mannose, galactose, and arabinose. The present study was designed to investigate the antioxidant capacity of AAP on blood lipid metabolism and lipoprotein lipase (LPL) activity in ICR mice fed cholesterol-enriched diet (CED) for the 1st time. Furthermore, the relationship between the atherosclerotic index (AI) and LPL activity to total antioxidant capacity (TAC) was studied. Thirty-six ICR mice were randomly assigned to 3 groups (n=12). The mice in control group (NG) received regular diet and the mice in model group (MG) received CED; these 2 groups were provided with distilled water by oral gavage. The experimental group (EG) was fed CED with oral gavage of AAP (120 mg/kg/d body weight) for an 8-wk period. After 2, 4, 6, and 8 wk, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels of the serum were determined by enzymatic methods. The results indicated that the polysaccharides significantly lowered the concentrations of serum TC and LDL-C compared with the CED control group (P<0.05). Moreover, oral administration of polysaccharides significantly improved TAC, LPL activity, and decreased MDA level, as well as AI. These conclusions revealed the beneficial effects ofAAP on the preventive actions against hypercholesterolemia.

The lipoprotein lipase deficient (LPL-/-) mice and high fat-diet (HFD) induced hypertriglyceridemic mice were used to investigate the effects of cardiotonic pill (CP) on RBC rheologic abnormalities. Mice were randomly divided into the following five groups: the control group; the untreated HFD group; the untreated LPL-/- group; the treated HFD group; and the treated LPL-/- group, and the treated HFD and LPL-/- mice were administered with CP twice a day (400 mg/kg/day) orally for four weeks. Then, plasma triglyceride (TG), RBC deformation index (DI), orientation index (DI)or and RBC electrophoretic time (EPT) were measured. Compared with the untreated HFD mice, TG level and EPT reduced and DI and (DI)or increased markedly in the treated HFD mice (P<0.05). However, compared with the untreated LPL-/- mice, these parameters in the treated LPL-/- mice had no statistically significant changes (P>0.05). Our data show that CP can lower plasma TG level and ameliorate RBC rheologic abnormalities in the HFD-induced hypertriglyceridemic mice, but it losses its capacity in the LPL deficient animals. The results indicate that LPL may be one of the important targets for CP regulating lipometabolism and rheologic abnormalities.

Apc gene-deficient Min and Apc(1309) mice feature a hyperlipidemic state with a markedly low expression level of lipoprotein lipase (LPL) compared to their wild-type counterparts. We previously showed that induction of LPL mRNA by peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonists or an LPL selective inducer suppresses both high serum lipid levels and intestinal polyp formation in these model animals. Since the general cyclooxygenase inhibitor, indomethacin, is known to suppress intestinal tumor development, but not to affect serum lipids, its influence in Min mice was here investigated. Treatment with 2.5, 5 and 10 ppm indomethacin in the diet for 14 weeks from 6 weeks of age caused significant dose-dependent reduction in serum triglycerides, along with a reduction in the numbers of intestinal polyps to 25% of the untreated control value. LPL mRNA levels in the liver were slightly increased by indomethacin treatment. We further performed oligonucleotide microarray analysis and quantitative PCR analysis and found 8 lipid metabolism-related genes, regulated by sterol regulatory element binding protein-1c, to be modulated by indomethacin-treatment in the Min mouse liver. Furthermore, TNFalpha was downregulated. These results indicate that indomethacin might suppress intestinal tumor formation together with a hyperlipidemic state by regulating LPL and other lipid metabolic factors., ((c) 2007 Wiley-Liss, Inc.)

The two-month effects of dietary fish protein and casein on VLDL, HDL(2) and HDL(3) compositions and hepatic lipase (HTGL) and tissue lipoprotein lipase (LPL) activities were examined in spontaneously hypertensive rats (SHR) at 4 wk of age. After 2 mo of experiment, the fish protein diet induced lower blood pressure (-14 %) as compared to casein. Liver triacylglycerol and total cholesterol concentrations were 1.37- and 1.71-fold lower in the fish protein group than in the casein group, respectively. Total cholesterol concentration in plasma was also diminished by fish protein (-21 %) and was reflected in HDL(2) fraction (-44 %). SHR fed the fish protein diet as compared with those fed casein, showed a significantly low HDL(3) particle number, as measured by diminished HDL(3) mass and apo A-I. The consumption of fish protein did not affect VLDL particle number, but significantly decreased VLDL-triacylglycerol (-32 %) and adipose tissue total lipid concentrations as compared to casein. This was accompanied by diminished HTGL and adipose tissue LPL activities (-10%, -91%, respectively). These data demonstrate that fish protein plays an antihypertensive role and reduces plasma and tissue lipid concentrations. Thus, a fish protein intake might be beneficial for patients with hypertension.

Background: Lipoprotein lipase (LPL) has a central role in the catabolism of triglyceride-rich lipoproteins. The enzyme is anchored to the vascular endothelium through interaction with heparan sulphate proteoglycans and is displaced from this interaction by heparin. When heparin is infused, there is a peak of LPL activity accompanied by a reduction in triglycerides (TG) during the first hour, followed by a decrease in LPL activity to a stable plateau during the remaining session while TG increase towards and beyond baseline. This suggests that tissue stores of LPL become depleted. It has been argued that low molecular weight (LMW) heparins cause less disturbance of the LPL system than conventional heparin does., Methods: We have followed LPL activity and TG during a dialysis-session with a LMW heparin (dalteparin) using the same patients and regime as in a previous study with conventional heparin, i.e. a primed infusion., Results: The shape of the curve for LPL activity resembled that during the earlier dialyses with conventional heparin, but the values were lower during dialysis with dalteparin. The area under the curve for LPL activity during the peak period (0-180 minutes) was only 27% and for the plateau period (180-240 minutes) it was only 36% of that observed with conventional heparin (p < 0.01). These remarkably low plasma LPL activities prompted us to re-analyze LPL activity and to measure LPL mass in frozen samples from our earlier studies. There was excellent correlation between the new and old values which rules out the possibility of assay variations as a confounding factor. TG increased from 2.14 mmol/L before, to 2.59 mmol/L after the dialysis (p < 0.01). From 30 minutes on, the TG values were significantly higher after dalteparin compared to conventional heparin (p < 0.05)., Conclusion: These results indicate that LMW heparins disturb the LPL system as much or more than conventional heparin does.

Objective: Lactation is associated with an increase in lipoprotein lipase (LPL) activity in the mammary gland (MG) and a decrease in adipose tissue because lactation redirects circulating substrates to the MG for milk synthesis. We investigated the effects of different dietary contents of trans-fatty acid (TFA) on LPL activity in maternal tissues and fatty acid composition in milk., Methods: Lactating rats were fed semisynthetic isocaloric diets containing 7% soy oil (control), 7% partially hydrogenated vegetable oil (7%-PHVO), 5% PHVO plus 2% soy oil (5%-PHVO), or 3.5% PHVO plus 3.5% soy oil (3.5%-PHVO). On lactation day 14, animals were decapitated and MG, liver, and parametrial adipose tissue were extracted to determine total lipid contents, percentages of TFA, and LPL activity. Milk lipid composition was examined by gas chromatographic analysis of the gastric content of 14-d-old suckling pups., Results: Maternal consumption of TFA increased dietary TFA incorporation in MG and liver and decreased it in parametrial adipose tissue. Diets with higher trans concentrations (7%-PHVO) significantly increased lipid content in the MG, and all groups fed trans-based diets showed significant increases in LPL activity in the MG. Although LPL increased in the MG, milk of rats fed TFA-based diets had significant decreases in the percentage of essential fatty acids., Conclusions: TFA intake during lactation alters maternal lipid metabolism and the percentage of essential fatty acids in milk; therefore, it is important to alert the population to avoid excessive intake of TFAs during lactation.

Lipoprotein lipase (LPL) secreted by macrophages in the arterial wall promotes atherosclerosis. We have shown that macrophages of patients with type 2 diabetes overproduce LPL and that metabolic factors, including glucose, stimulate macrophage LPL secretion. In this study, we determined the effect of advanced glycation end products (AGEs) on LPL expression by macrophages cultured in a high-glucose environment and the molecular mechanisms underlying this effect. Our results demonstrate that AGEs potentiate the stimulatory effect of high glucose on murine and human macrophage LPL gene expression and secretion. Induction of macrophage LPL mRNA levels by AGEs was identical to that elicited by physiologically relevant modified albumin and was inhibited by anti-AGE receptor as well as by antioxidants. Treatment of macrophages with AGEs resulted in protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activation. Inhibition of these kinases abolished the effect of AGEs on LPL mRNA levels. Finally, exposure of macrophages to AGEs increased the binding of nuclear proteins to the activated protein-1 consensus sequence of the LPL promoter. This effect was inhibited by PKC and MAPK inhibitors. These results demonstrate for the first time that AGEs potentiate the stimulatory effect of high glucose on macrophage LPL expression. This effect appears to involve oxidative stress and PKC/MAPK activation., (Copyright 2004 American Society for Biochemistry and Molecular Biology, Inc.)

A major factor contributing to cardiovascular mortality in type 2 diabetes is dyslipidemia, characterized by low HDL cholesterol and high triglycerides, rather than elevated LDL cholesterol. Lipoprotein lipase (LPL) is the rate-limiting enzyme of triglyceride removal from plasma and has been implicated in atherosclerosis. Since treatment with statins significantly reduces cardiovascular morbidity in diabetes, we analyzed the lipid profile and LPL activities in 61 patients with type 2 diabetes before and 8 weeks after initiation of atorvastatin (40 mg) or placebo treatment. Lipid parameters and LPL activity were unchanged under treatment with placebo. Atorvastatin treatment resulted in a 30% reduction of total and a 45% reduction of LDL cholesterol (6.06 +/- 1.39 mmol/L versus 4.14 +/- 1.27 mmol/L and 4.11 +/- 1.13 mmol/L versus 2.27 +/- 0.89 mmol/L, both P < 0.0001). Triglycerides and VLDL cholesterol were also significantly reduced by statin therapy (2.24 +/- 2.11 mmol/L versus 1.82 +/- 1.46 mmol/L and 1.08 +/- 1.56 mmol/L versus 0.67 +/- 0.66 mmol/L, both P < 0.05). HDL cholesterol was not different between the atorvastatin and the placebo group. Compared to baseline, LPL activity was increased by 25% after atorvastatin treatment (213.0 +/- 28.1 nmol/mL/min versus 171.9 +/- 17.7 nmol/mL/min, P < 0.01). Our data demonstrate that atorvastatin induces a significant improvement of diabetic dyslipidemia and a significant increase of LPL activity. Since low LPL activity indicates an increased cardiovascular risk, the statin-mediated increase in LPL activity may help to explain the reduction of CAD in diabetic patients treated with statins., (Copyright 2004 Elsevier Ireland Ltd)

When food was removed from young rats in the early morning, adipose tissue tumor necrosis factor (TNF)-alpha activity increased 50% and lipoprotein lipase (LPL) activity decreased 70% in 6 h. There was a strong negative correlation between the TNF-alpha and LPL activities. Exogenous TNF-alpha further decreased LPL activity. Pentoxifylline, known to decrease production of TNF-alpha, had no effect on LPL activity in fed rats but almost abolished the rise of TNF-alpha and the decrease of LPL activity in rats deprived of food. The specific activity of LPL decreased from 0.92 mU/ng in fed rats to 0.35 and 0.24 mU/ng in rats deprived of food given saline or TNF-alpha, indicating a shift in the LPL molecules toward an inactive state. Lipopolysaccharide increased adipose tissue TNF-alpha and decreased LPL activity. Both of these effects were strongly impeded by pretreatment of the rats with pentoxifylline, or dexamethasone. Pretreatment of the rats with actinomycin D virtually abolished the response of LPL activity to food deprivation or exogenous TNF-alpha. We conclude that food deprivation, like lipopolysaccharide, signals via TNF-alpha to a gene whose product causes a rapid shift of newly synthesized LPL molecules toward an inactive form and thereby shuts down extraction of lipoprotein triglycerides by the adipose tissue.

Previous studies have indicated a relationship between cocaine- and amphetamine-related transcript (CART) and leptin. The present study used quantitative PCR and in situ hybridization to examine this CART-leptin relationship in different animal models. With CART injection, the function of this pathway was also investigated. The results demonstrate that CART mRNA in the arcuate nucleus (ARC) was significantly increased in subjects fed a high-fat diet (HFD) compared to low-fat diet (LFD). It was also elevated in obese vs. lean rats and in normal-weight obesity-prone vs. obesity-resistant rats. In each group tested, CART mRNA in the ARC was positively correlated specifically with circulating levels of leptin. Its close association specifically with leptin was further supported by a stimulatory effect of this hormone on CART expression. This leptin-CART relationship in the ARC, in contrast, was less consistent or undetectable in the paraventricular nucleus and lateral hypothalamus. Central injection of CART peptide (55-102) increased circulating non-esterified fatty acid levels and decreased lipoprotein lipase activity in adipose tissue. These results suggest that, on a fat-rich diet, this leptin-CART pathway originating in the ARC inhibits excessive body fat accrual by causing a shift from lipid storage toward lipid mobilization.

The effect of Acanthopanax senticosus (AS) leaves on lipoprotein lipase (LPL) was investigated in 3T3-L1 adipocytes. A water extract of AS leaves increased the LPL activity in culture medium of adipocytes in a dose- and time-dependent manner. The AS extract contained heparin-like LPL releasing components, however, the increase of medium LPL activity was continued up until 12 h, in contrast to the rapid decline after heparin treatment. The increase of LPL mRNA was also observed after AS extract treatment, suggesting that LPL induction occurs at the transcriptional level. The AS extract could partially reverse the LPL suppression by tumour necrosis factor-alpha in 3T3-L1 adipocytes. These results of an AS extract-induced increase of LPL activity in vitro suggest the possible action of AS as a facilitator of plasma triglyceride clearance., (Copyright 2004 John Wiley & Sons, Ltd.)

1. The study was conducted to investigate the pharmacokinetics and metabolism of NO-1886 (diethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) in cynomolgus monkeys. 2. After single intravenous administration of NO-1886 at a dose of 3 mg kg(-1), the total clearance (CL(tot)), area under the plasma concentration-time curve (AUC(0-)(t)), half-life (t(1/2)), and volume of distribution (V(d)) in cynomolgus monkeys were 531 ml h(-1) kg(-1), 5.63 micro g h ml(-1), 0.96 h and 679 ml kg(-1), respectively. The AUC(0-)(t) for oral administration of NO-1886 (3 mg kg(-1)) was 4.23 micro g h ml(-1) and the bioavailability was 75%. 3. M-2 (ethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) and M-3 (4-[(diethoxy-phosphoryl) methyl)] benzoic acid) were present as metabolites in plasma and urine. In faeces, M-2 was present but M-3 was not. 4. The major metabolite of NO-1886 in liver S9 or microsomes was M-2 in the presence of NADPH. On the other hand, M-3 was formed in the absence of NADPH in liver S9 or microsomes and its formation was inhibited by bis-( p-nitrophenyl) phosphate (BNPP) in liver S9, suggesting that the formation of M-3 was catalysed by carboxylesterase. 5. The findings suggest that the main metabolic pathway of NO-1886 in cynomolgus monkeys is the O-deethylation of NO-1886 to M-2, as in rats and humans, and that the hydrolysis of the amide bond is a minor metabolic pathway.

Background: We previously reported that the tamoxifen treatment caused a decrease in lipoprotein lipase (LPL) activity and an increase in LPL mass. We hypothesized that tamoxifen may increase the quantity of inactive LPL., Methods: Lipoprotein lipase in post-heparin plasma usually exists in both monomeric and dimeric forms, which may be separated on a heparin-Sepharose column with different salt concentrations. Lipoprotein lipase in post-heparin plasma from postmenopausal patients with hypertriglyceridemia treated with or without tamoxifen was incubated with or without 4-hydroxy-tamoxifen (4-OHT), the monomers and dimers were separated on a heparin-Sepharose column and their masses were measured., Results: The masses of total LPL and dimeric LPL of tamoxifen-treated patients were significantly higher than those of control subjects. Monomeric LPL of tamoxifen-treated patients passed more slowly through the heparin-Sepharose column compared with that of control subjects. The ratio of monomeric LPL to dimeric LPL of tamoxifen-treated patients was 0.61, significantly lower than that of control subjects, which was 1.45 (p<0.01). In addition, monomeric LPL incubated with 4-OHT passed more slowly through the heparin-Sepharose column compared with that incubated without 4-OHT., Conclusion: Tamoxifen influences the affinity of LPL for heparin.

Large (ca. 120 nm) and small (ca. 35 nm) emulsions consisting of triolein (TO) and phosphatidylcholine (PC) were prepared as the primary protein-free models of chylomicrons and their remnants, respectively. Lipoprotein lipase (LPL)-mediated lipolysis of emulsion TO was retarded in chylomicron-free human plasma compared with the hydrolysis activated by isolated apolipoprotein C-II (apoC-II). In 30% plasma, free fatty acid (FFA) release rate was higher for large emulsions than for small ones, while both emulsions were hydrolyzed at similar rates in the presence of isolated apoC-II. Isolated apolipoprotein C-III (apoC-III) or apolipoprotein E (apoE) worked as LPL-inhibitor of the lipolysis activated by apoC-II. It was also observed that apolipoprotein A-I (apoA-I) showed distinct inhibitory effects on the lipolysis of large and small emulsions: more effective inhibition for small emulsions. Kinetic analyses showed that K(m)(app) and V(max)(app) for the lipolysis of emulsions were lower in the presence of 30% plasma than isolated apoC-II. ApoA-I also markedly decreased K(m)(app) and V(max)(app) for LPL-catalyzed hydrolysis of both emulsions. In chylomicron-free serum, the density of bound apoA-I at small emulsion surfaces was about three fold greater than large emulsion surfaces, but the binding densities of apoC-II, apoC-III and apoE were less for small emulsion surfaces than for large ones, suggesting that apoA-I preferentially binds to small particles and displaces other exchangeable apolipoproteins from particle surfaces. These results indicate that, in addition to the well known inhibitory effects of apoC-III and apoE, apoA-I in plasma regulates the lipolysis of triglyceride (TG)-rich emulsions and lipoproteins in a size-dependent manner.

We have compared lipoprotein metabolism in, and susceptibility to atherosclerosis of, two strains of male Golden Syrian hamster, the Bio F(1)B hybrid and the dominant spot normal inbred (DSNI) strain. When fed a normal low-fat diet containing approximately 40 g fat and 0.3 g cholesterol/kg, triacylglycerol-rich lipoprotein (chylomicron+VLDL) and HDL-cholesterol were significantly higher (P<0.001) in Bio F(1)B hamsters than DSNI hamsters. When this diet was supplemented with 150 g coconut oil and either 0.5 or 5.0 g cholesterol/kg, significant differences were seen in response. In particular, the high-cholesterol diet produced significantly greater increases in plasma cholesterol and triacylglycerol in the Bio F(1)B compared with the DSNI animals (P=0.002 and P<0.001 for cholesterol and triacylglycerol, respectively). This was particularly dramatic in non-fasting animals, suggesting an accumulation of chylomicrons. In a second experiment, animals were fed 150 g coconut oil/kg and 5.0 g cholesterol/kg for 6 and 12 months. Again, the Bio F(1)B animals showed dramatic increases in plasma cholesterol and triacylglycerol, and this was confirmed as primarily due to a rise in chylomicron concentration. Post-heparin lipoprotein lipase activity was significantly reduced (P<0.001) in the Bio F(1)B compared with the DSNI animals at 6 months, and virtually absent at 12 months. Bio F(1)B animals were also shown to develop significantly more (P<0.001) atherosclerosis. These results indicate that, in the Bio F(1)B hybrid hamster, cholesterol feeding reduces lipoprotein lipase activity, thereby causing the accumulation of chylomicrons that may be associated with their increased susceptibility to atherosclerosis.

The synthetic compound NO-1886 is a lipoprotein lipase activator that lowers plasma triglycerides and elevates high-density lipoprotein cholesterol (HDL-C). Recently, the authors found that NO-1886 also had an action of reducing plasma glucose in high-fat/high-sucrose diet-induced diabetic rabbits. In the current study, we investigated the effects of NO-1886 on insulin resistance and beta-cell function in rabbits. Our results showed that high-fat/high-sucrose feeding increased plasma triglyceride, free fatty acid (FFA), and glucose levels and decreased HDL-C level. This diet also induced insulin resistance and impairment of acute insulin response to glucose loading. Supplementing 1% NO-1886 into the high-fat/high-sucrose diet resulted in decreased plasma triglyceride, FFA, and glucose levels and increased HDL-C level. The authors also found a clear increased glucose clearance and a protected acute insulin response to intravenous glucose loading by NO-1886 supplementation. These data suggest that NO-1886 suppresses the elevation of blood glucose in rabbits induced by feeding a high-fat/high-sucrose diet, probably through controlling lipid metabolism and improving insulin resistance., (Copyright 2003 Taylor and Francis)

Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors which mediate pleiotropic effects including regulation of genes involved in lipid metabolism and control of inflammation. In the present study, we measured the in vitro effects of PPAR alpha and gamma ligands on macrophage lipoprotein lipase (LPL) expression. Human monocyte-derived macrophages (MDM) were cultured for 1-3 days in the presence of PPAR alpha and gamma ligands. At the end of these incubation periods, extracellular LPL immunoreactive mass/activity and LPL mRNA levels were measured. Incubation of human MDM with PPAR alpha and gamma ligands stimulated, in a time- and dose-dependent manner, human MDM LPL mass and activity. These agents also significantly increased macrophage LPL mRNA expression. In THP-1 cells treated with PPAR alpha and gamma ligands, enhanced nuclear protein binding to the peroxisome proliferator responsive element (PPRE) of the human LPL promoter was observed. Furthermore, in these cells, a decreased rate of decay of LPL mRNA was documented. Overall, these results demonstrate that PPAR alpha and gamma activators increase macrophage LPL secretion. Given the proatherogenic effect of vascular wall LPL, better understanding of the role of PPARs in the regulation of macrophage LPL expression could lead to the development of new approaches in the prevention and treatment of atherosclerosis.

Exercise decreases plasma total cholesterol and triglycerides, and simultaneously, increases high density lipoprotein (HDL) cholesterol. As a result, exercise is believed to aid in preventing atherosclerosis. However, we do not know whether exercise protects against the development of atherosclerosis in the elderly. The aim of this study was to ascertain whether the lipoprotein lipase activator NO-1886 had an effect on the prevention of atherosclerosis in aged rats which undergo exercise. Exercise for 3 months did not affect plasma lipids but decreased the accumulation of visceral fat in 2-year-old rats (aged rat). Exercise also resulted in an elevation of plasma lipid peroxide (LPO) levels and impaired the endothelium-dependent relaxation of the thoracic aorta caused by acetylcholine in aged rats. On the other hand, NO-1886 decreased plasma triglycerides and increased HDL cholesterol and suppressed the elevation of plasma LPO levels caused by exercise. Furthermore, NO-1886 prevented impaired endothelium-dependent relaxation caused by exercise. In summary, the results of our study indicate that exercise may cause impaired endothelium-dependent relaxation by elevation of LPO in aged rats, and that NO-1886 prevents this impaired endothelium-dependent relaxation of aorta by reducing plasma triglycerides, elevating HDL cholesterol, and suppressing the elevation of plasma LPO caused by exercise.

Background: We investigated whether variations in lipoprotein lipase activity, a key post-prandial enzyme involved in the removal of circulating dietary triglycerides, could contribute to the previously described nocturnal lipid intolerance., Methods: We studied lipoprotein lipase activity in 12 healthy volunteers (five women, seven men) at 11:30 h and 23:30 h on two separate occasions. Subjects consumed a high-fat mixed meal at 07:30 h for the morning study or 19:30 h for the evening study. Then, after a 4-h fast, subjects were given an intravenous bolus of 7,500 U heparin. Blood samples were collected before and 15 min after heparin administration for measurement of lipoprotein lipase, hepatic lipase, triglycerides and non-esterified fatty acids concentrations., Results: Post-prandial post-heparin lipoprotein lipase activity was greater in the morning than in the evening (16.5 +/- 1.4 versus 14.4 +/- 1.0 micromol oleate/mL/h; P< 0.05). Post-prandial post-heparin hepatic lipase activity was also greater in the morning than in the evening (8.7 +/- 1.5 versus 81 +/- 1.6 micromol oleate/mL/h; P= 0.002). There were no other significant diurnal differences., Conclusion: We report a diurnal variation in post-prandial lipoprotein lipase activity. This is consistent with the notion that decreased nocturnal insulin sensitivity extends to insulin's actions on lipoprotein lipase and provides a possible explanation for nocturnal lipid intolerance.

The aim of this study was to establish the dose-response relationship between fat intake and heparin-released plasma lipoprotein lipase (LPL) activity in horses. Eight mature trotters were fed 4 rations with different fat levels (3.0, 5.0, 7.7, or 10.8% fat in the dry matter) according to a 4 X 4 Latin square design. The experimental rations consisted of hay and different concentrates; the concentrates and hay were given in a 3:1 ratio on an energy basis. Soybean oil was added to the concentrates at the expense of isoenergetic amounts of glucose. Blood samples were taken at the end of each dietary period, which lasted 3 weeks. Fat feeding was found to increase heparin-released plasma LPL activity in a dose-dependent fashion. When the data from this study and previous studies were combined it was calculated that an increase in fat intake by 1 g/kg dry matter is associated with an increase in LPL activity by 0.98 micromol fatty acid released-mL(-1) x h(-1). Fat feeding raised the plasma concentrations of total cholesterol, high-density lipoprotein cholesterol, and phospholipids. Diet did not have a statistically significant effect on plasma triacylglycerol concentrations. The results are discussed in the light of the possible enhancing effect of fat feeding on the oxidative capacity of skeletal muscle.

Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid increase in serum triglyceride levels. LG268 has no effect on hepatic triglyceride production but suppresses post-heparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished peripheral processing of plasma very low density lipoproteins particles. Treatment of diabetic rats with rexinoids suppresses skeletal and cardiac muscle but not adipose tissue LPL activity. This effect is independent of changes in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surface (i.e., heparin-releasable) LPL activity without altering LPL mRNA. This effect is very rapid (t(1/2) = 2 h) and is blocked by the transcriptional inhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest that skeletal muscle may be an important target of rexinoid action. In addition, these data underscore that the metabolic consequences of RXR activation are distinct from either retinoic acid receptor or peroxisome proliferator-activated receptor activation.

Hyperlipidemia associated with nephrotic syndrome may play a role in the deterioration of renal function. Tsutsumi et al have previously reported that the novel compound NO-1886 increases lipoprotein lipase (LPL) activity, resulting in a reduction of plasma triglycerides and an elevation of high-density lipoprotein (HDL) cholesterol in normal rats. The aim of this study was to ascertain whether NO-1886 suppresses the renal injury by treatment of the hyperlipidemia in an Adriamycin (Kyowa Hakko Kogyo, Tokyo, Japan) induced nephrosis rat model fed a high-protein diet that induced renal dysfunction and tubulointerstitial injury. Administration of Adriamycin caused hyperlipidemia, proteinuria, and edema with ascites in rats in 4 weeks. Furthermore, a combination of Adriamycin and a high-protein diet increased plasma creatinine and blood urea nitrogen (BUN) and decreased plasma albumin. Histologically, in Adriamycin-treated rats, marked interstitial cellular infiltration, tubular lumen dilation, and tubular cast formation in the kidney were observed. NO-1886 decreased plasma triglyceride and increased HDL cholesterol in Adriamycin-induced nephrotic rats. NO-1886 treatment reduced plasma creatinine and BUN levels and increased plasma albumin in Adriamycin-treated rats; it also ameliorated the ascites and proteinuria. Histologically, NO-1886-treated rats showed a quantitatively significant preservation of tubulointerstitial lesions. These data suggest that NO-1886 may have a protective effect against Adriamycin-induced nephrosis with tubulointerstitial nephritis in rats by a modification of the plasma lipid disorder.

Objectives: After 10 d of orlistat administration (120 mg three times/day), the primary objective was to determine the drug's effect on postprandial plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities on day 10 after an oral fat-load. The secondary objectives were to determine the effects of orlistat on 12 h postprandial measures of: (1) preheparin HTGL and LPL; and (2) serum triglycerides, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and free fatty acids., Methods: Twenty-four normal-weight, healthy male volunteers were randomized to either 120 mg orlistat (n=12) or placebo (n=12) three times a day with meals for 10 d. Preheparin LPL and HTGL activities and LPL specific activity were measured in the fasted state on days 1, 5, and 10. On days 5 and 10 the study medication (orlistat or placebo) was taken at the beginning of a fat-rich breakfast and serum lipid and lipoprotein levels monitored for 12 h postprandially. On day 10, 15 min postheparin HTGL activity was measured 8 h after the fat-rich breakfast., Results: No differences were found between groups in fasting levels of preheparin LPL or HTGL activity or in LPL-specific activity on days 1, 5 and 10. No difference was found between the two treatment groups in postheparin HTGL activity 8 h after the fat-rich breakfast. Also, no differences were found between the two groups in plasma triglycerides or lipoproteins., Conclusion: The results indicate that the oral administration of orlistat (120 mg t. i.d.) does not significantly alter plasma triglycerides or lipoproteins, and that the inhibitory effect of orlistat on lipases is limited to the gastrointestinal tract and is not manifested systemically.

In recent years, it has been established that lipoprotein lipase (LPL) is partly associated with circulating lipoproteins. This report describes the effects of physiological amounts of very low density lipoprotein (VLDL)-bound LPL on the cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester transfer (CET) from high density lipoprotein (HDL) to VLDL. Three patients with severe LPL deficiency exhibited a strong decrease in net mass CET that was more than 80% lower than that of common hypertriglyceridemic subjects. Recombination experiments showed that this was due to an abnormal behavior of the VLDL fraction. Replacement of the latter by normal VLDL totally normalized net mass CET. We therefore prepared VLDL containing controlled amounts of bound LPL that we used as CE acceptors in experiments involving unidirectional radioisotopic CET measurements. These were carried out either in the absence or in the presence of inhibitors of LPL lipolytic activity. When LPL-induced lipolysis was totally blocked, the stimulating effect of the enzyme on the CETP-dependent CET was only reduced by about 50%, showing that it did not entirely result from its lipolytic action. These data were dependent upon neither the type of LPL inhibitor (E600 or THL) nor the source of CETP (delipidated plasma or partially purified CETP). Thus, in addition to the well-known stimulating effect of LPL-dependent lipolysis on CET, our work demonstrates that physiological amounts of VLDL-bound LPL may facilitate CET through a mechanism partially independent of its lipolytic activity.

The role of gemfibrozil, a hypotriglyceridemic drug, in synthesis, secretion and catabolism of triacylglycerols (TG) in rats was assessed. Chow diet-fed Sprague-Dawley rats were given various doses of gemfibrozil (10, 30 and 100 mg/kg body weight) for 2 weeks. Rats receiving the drug at the lowest dose significantly lowered the concentration of serum TG and apolipoprotein (apo) B in comparison with control rats. Synthesis of fatty acids from [14C]acetate and esterification of [14C]oleate to TG by the liver were not suppressed by the drug. Secretion rates of TG and apo B, measured by the Triton method, were suppressed at the highest dose. Lipoprotein lipase activity of the acetone powder prepared from adipose tissue was not influenced by the drug. These results indicate that the primary cause of hypotriglyceridemic action of gemfibrozil is not due to suppressing synthesis and secretion of TG by the liver or enhancing lipoprotein lipase activity in adipose tissues.

The effect of ginseng saponins isolated from red ginseng (a steamed and dried root of Panax ginseng) has been studied in a cyclophosphamide (CPM)-induced hyperlipidemia model in fasted rabbits. In this model, chylomicrons and very low density lipoprotein (VLDL) accumulation was known to occur as a result of reduction in lipoprotein lipase (LPL) activity in the heart and heparin-releasable heart LPL. Oral administration of ginseng saponins at a dose of 0.01 g/kg for 4 weeks was found to reverse the increase in serum triglycerides (TG) and concomitant increase in cholesterol produced by CPM treatment, especially in chylomicrons and VLDL. In addition, ginseng saponins treatment led to a recovery in postheparin plasma LPL activity and heparin-releasable heart LPL activity, which were markedly reduced by CPM treatment. In rats given 15% glycerol/15% fructose solution, postheparin plasma LPL activity declined to two third of normal rats, whereas ginseng saponins reversed it to normal levels. In the present study we first demonstrated that ginseng saponins sustained LPL activity at a normal level or protected LPL activity from being decreased by several factors, resulting in the decrease of serum TG and cholesterol.

Background: We reported in previous studies that plasma triglyceride levels, as well as remnant-like particles-cholesterol (RLP-C) and -triglyceride (RLP-TG) levels, were significantly lower in maintenance hemodialysis (HD) patients treated with erythropoietin (EPO) than in HD patients treated without EPO. However, little is known about the mechanisms underlying the improvements in abnormal RLP metabolism in HD patients. This study investigates whether EPO supplement therapy in cases of uremic anemia increases the plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) levels in HD patients., Methods: Twenty HD patients who had not previously received EPO were divided into two groups according to the stage of HD: 12 at the initial stage, defined as a mean HD duration of 0.35 +/- 0.68 months (range of 0 to 2.47 months), and 8 at the maintenance stage, defined as a mean HD duration of 114.1 +/- 91.9 months (range of 13.0 to 253.9 months). Fasting plasma was collected from the HD patients prior to the start of the EPO supplement therapy and at one month after the therapy. RLP-C levels were determined using a RLP-C JIMRO II kit. Fasting plasma was also collected from the HD patients 10 minutes after an intravenous injection of heparin (30 U/kg body wt). Plasma LPL levels were determined using an enzyme immunoassay, and HTGL levels were determined using a modified version of the Hernell et al method., Results: Plasma RLP-C levels showed a tendency to decrease after the start of the EPO supplement therapy in HD patients at the maintenance stage. Plasma LPL levels were significantly higher in the two groups of HD patients one month after the start of the EPO supplement therapy than in the same patients prior to the start of the EPO supplement therapy. Plasma HTGL levels were significantly higher in HD patients at the maintenance stage one month after the start of the EPO supplement therapy than in HD patients at the maintenance stage prior to the start of the EPO supplement therapy., Conclusions: The results of this study suggest that the EPO supplement therapy may reduce plasma RLP-C levels by increasing the plasma LPL and HTGL levels in maintenance-stage HD patients.

Statins are hypolipidemic drugs which not only improve cholesterol but also triglyceride levels. Whereas their cholesterol-reducing effect involves inhibition of de novo biosynthesis of cellular cholesterol through competitive inhibition of its rate-limiting enzyme 3-hydroxy-3-methylglutaryl CoA reductase, the mechanism by which they lower triglycerides remains unknown and forms the subject of the current study. Treatment of normal rats for 4 days with simvastatin decreased serum triglycerides significantly, whereas it increased high density lipoprotein cholesterol moderately. The decrease in triglyceride concentrations after simvastatin was caused by a reduction in the amount of very low density lipoprotein particles which were of an unchanged lipid composition. Simvastatin administration increased the lipoprotein lipase mRNA and activity in adipose tissue and heart. This effect on lipoprotein lipase was accompanied by decreased mRNA as well as plasma levels of the lipoprotein lipase inhibitor apolipoprotein C-III. These results suggest that the triglyceride-lowering effect of statins involves a stimulation of lipoprotein lipase-mediated clearance of triglyceride-rich lipoproteins.

Lipoprotein lipase (LPL) is involved in clearing triglyceride-rich chylomicrons and very-low-density lipoprotein particles from the bloodstream, providing free fatty acids to particular adipose tissue for storage and to skeletal muscle tissue for oxidation and energy production. Although the same gene (chromosome 8p22) encodes LPL, the enzyme activity is regulated in a tissue-specific manner. Dysfunction of the LPL enzyme has been implicated in the pathogenesis of dyslipidemia (high triglyceride and low high-density lipoprotein (HDL) cholesterol), early arteriosclerosis, and the pathogenesis of obesity. Treatment with growth hormone (GH) both in vivo and in vitro results in a pronounced reduction (often up to 50%) of LPL activity in adipose tissue in humans. The specific level of messenger ribonucleic acid, however, is not generally affected by GH treatment in adipose tissue, indicating that the effect of GH is mediated at a post-translational level. The GH-mediated reduction in adipose tissue LPL activity may be involved in the reduction in adipose tissue mass commonly seen after prolonged GH treatment in GH-deficient adults and GH treatment in obese subjects. LPL activity in adipose and skeletal muscle tissue is generally regulated in a reciprocal manner by, for example, fasting, feeding, insulin and epinephrine. A high level of LPL activity, particularly in skeletal muscle tissue, has been found to be associated with a beneficial lipoprotein profile (low triglyceride and high HDL cholesterol). In investigations where obese but otherwise healthy women were treated with GH, and in another study where adults with GH deficiency were treated for 4 months with GH, we found no effects of GH on either skeletal muscle LPL activity nor on skeletal muscle LPL gene expression. In conclusion, GH has a pronounced inhibitory effect on adipose tissue LPL activity, which is mediated at a post-translational level. The GH-induced reduction in adipose tissue mass may be partly mediated by this effect on adipose tissue LPL. GH has no effects on LPL activity in skeletal muscle, which may be related to the fact that GH has no or only minor effects on plasma triglyceride and HDL cholesterol levels. Finally, GH is not, unlike for example insulin and catecholamines, involved in antagonistic regulation of LPL in muscle and adipose tissue.

Lipoprotein lipase (LPL) is a key enzyme in the regulation of the flux of fatty acids. LPL hydrolyses triglycerides in chylomicrons and very-low-density lipoproteins (VLDL), forming intermediate- (IDL) and low-density lipoproteins (LDL). Hepatic lipase (HL) is a related enzyme with a more restricted tissue distribution than LPL; HL is mainly engaged in the turnover of IDL and of high-density lipoproteins (HDL). Both enzymes can be released from their endothelial sites by heparin and their activities measured separately in post-heparin plasma (PHP). The PHP-LPL activity decreases in hypophysectomized rats and this effect is reversed by growth hormone (GH) therapy. However, GH seems to have no effect, or an inhibitory effect, on PHP-LPL activity in humans. Muscle and adipose tissues are the main sources of PHP-LPL activity. One week of GH therapy of hypophysectomized rats increases skeletal muscle and heart LPL activity. In this model, GH has little or no effect on LPL activity in adipose tissue. However, GH has been shown to decrease LPL activity in isolated rat adipose tissue. Insulin-like growth factor-I therapy decreases and insulin therapy increases LPL activity in adipose tissue of hypophysectomized rats, whereas these therapies have no effect on LPL activity in muscle tissue. The LPL activity in human adipose tissue is reduced both in vivo and in vitro after administration of GH while the LPL mRNA level is unchanged. The effect of GH on HL activity has been studied in PHP and liver. Several studies in the rat indicate that GH increases PHP-HL and liver HL activity, at least partly at the level of mRNA expression. In humans, GH has been shown to have variable effects on PHP-HL activity; this variability is probably to some extent dependent on different experimental set-ups. Although GH therapy increases hepatic secretion of VLDL, serum triglyceride levels decrease as a result of GH therapy in the hypophysectomized rat. An increase in HL and LPL activity by GH therapy is in line with these findings. In summary, GH is involved in the regulation of both LPL and HL activity but the effects and mechanisms of action of GH in the regulation of LPL and HL activity in different tissues are not yet fully elucidated.

Sprague-Dawley rats were fed purified diets varying in both protein (20%) and lipid (11%) content for 28 d to verify the independent and interactive effects of dietary proteins and lipids on serum and hepatic lipids, and on tissue lipoprotein lipase (LPL) activity in both fasted and postprandial states. These diets consisted of either casein-menhaden oil, casein-coconut oil, soy protein-menhaden oil (SPMO), soy protein-coconut oil, cod protein-menhaden oil, or cod protein-coconut oil. A randomized 3 x 2 factorial design was used. A significant protein-lipid interaction was seen on serum triglyceride levels: menhaden oil, compared with coconut oil, induced a decrease in serum triglyceride levels when combined with soy protein but not when combined with cod protein and casein. The lower serum triglyceride concentrations observed in the SPMO-fed rats could be the result of decreased hepatic triglycerides when soy protein was compared with casein and when menhaden oil was compared with coconut oil. Total LPL activity in the heart was higher in menhaden oil-fed rats than in coconut oil-fed rats in the postprandial state. The higher LPL activity in the heart could, however, explain only 10% of the reduction of serum triglycerides, contributing slightly to the lowering effects of SPMO diet on serum triglycerides. Therefore, the present results indicate that dietary proteins can modulate the effects of fish oil on triglyceridemia in the rat, and that could be mainly related to specific alterations in hepatic lipid concentrations.

Lipoprotein lipase (LPL) hydrolyzes the triacylglycerol component of circulating lipoprotein particles, mediating the uptake of fatty acids into adipose tissue and muscle. Insulin is the principal factor responsible for regulating LPL activity in adipose tissue, yet the mechanisms whereby insulin controls LPL expression are unknown. The current studies used wortmannin, a specific inhibitor of phosphatidylinositol (PI) 3-kinase, and rapamycin, a specific inhibitor of activation of phosphoprotein 70 ribosomal protein S6 kinase (p70s6k), to explore some of the components of the insulin signaling pathway controlling LPL activity in adipose cells. Preincubation of isolated rat adipose cells with wortmannin completely abrogated the stimulation of LPL activity by insulin, while preincubation with rapamycin caused approximately a 60% inhibition of insulin-stimulated LPL activity. Thus, the current studies show that the regulation of adipose tissue LPL by insulin is mediated via a wortmannin-sensitive pathway, most likely PI 3-kinase, and that a rapamycin-sensitive pathway, most likely p705s6k, constitutes an important downstream component in the insulin signaling pathway through which LPL is regulated.

Lipoprotein lipase (LPL) is an adipocyte enzyme that cleaves fatty acids from circulating lipoproteins. Fatty acids enter the cell to be oxidized or esterified. Hormone-sensitive lipase (HSL) is an adipocyte enzyme that cleaves fatty acids from intracellular triacylglycerol. The HSL is activated by phosphorylation. Assays for the two lipases are complex because the hydrophobic substrate, triacylglycerol, must be presented as a gum-based suspension or as a detergent-based emulsion to a relatively hydrophilic enzyme. A convenient, stable glycerol/phospholipid suspension of the substrate was used for measurement of porcine adipose tissue LPL and HSL in vitro. This substrate was excellent for LPL. It produced rates five times those using a more complex and less convenient gum-based substrate suspension. The LPL activity was released by heparin, had a pH optimum of approximately 8.5, was activated by serum, and was inhibited by NaCl and protamine. This LPL assay measures enzyme capacity. The same substrate was used to measure an adipose tissue lipase activity that had a pH optimum below 7, was not activated by serum, and was not inhibited by NaCl or protamine. These are all characteristics of HSL. Despite the convenience, this substrate was not appropriate for porcine adipose tissue HSL because the rates were only 30 to 50% of those produced with a more complex, less convenient gum-based substrate suspension. Furthermore, incubation of enzyme or tissue slices with insulin, or agents that elevate cAMP concentration, did not modulate this lipase activity, as expected. These incubations poorly modulated LPL activity.

Cardiovascular diseases are the leading cause of morbidity and mortality in diabetes. Lipoprotein lipase (LPL), a major secretory product of macrophages, has been suggested to play a key role in the development of atherosclerosis. In the present study, we evaluated the effect of high glucose on macrophage LPL mRNA expression and secretion. Exposure of murine J774 macrophages to high D-glucose concentrations (20-30 mmol/l) resulted in a dramatic upregulation of LPL mRNA expression and immunoreactive mass. This effect was not observed when these cells were incubated in the presence of L-glucose or mannitol. High glucose concentrations were also found to enhance LPL gene expression and immunoreactive mass in human monocyte-derived macrophages. J774 cells cultured in a high glucose environment expressed increased c-fos mRNA levels. Treatment of these cells with c-fos antisense DNA or protein kinase C inhibitor inhibited the stimulatory effect of glucose on LPL mRNA expression. In J774 cells exposed to high glucose concentrations, enhanced nuclear protein binding to the AP-1-responsive region of the murine LPL promoter was observed, while LPL mRNA stability remained unchanged. Overall, these results demonstrate that high glucose upregulates macrophage LPL gene expression and immunoreactive mass and that this effect involves transcriptional events.

Lipoprotein lipase (LPL) is an endothelial-bound enzyme that is rate determining for the clearance of triacylglycerol-rich lipoproteins. Previous studies using rats with streptozotocin (STZ)-induced diabetes have reported inconsistent effects on cardiac LPL activity or immunoreactive protein. To examine the contribution of the severity and duration of diabetes on cellular and heparin-releasable cardiac LPL activity, Wistar rats were administered a high (100 mg/kg; D100) or moderate (55 mg/kg; D55) dose of STZ, and LPL activity was examined at various times after diabetes induction. Heparin perfusion of the isolated Langendorff control heart induced the release of LPL activity as an initial fast phase followed by a slow phase of release. With increasing age, the second phase of LPL release became more pronounced. Severe STZ-induced diabetes reduced heparin-releasable LPL activity by 1 week in the D100 rats. However, in D55 rat hearts, peak heparin-releasable LPL activity was higher than that in control animals at 2 and 12 weeks after STZ injection, with a complete absence of the delayed phase at 12 weeks. The elevated heparin-releasable LPL peak could not be explained by an enhanced LPL synthesis because both cellular and surface-bound LPL activities in myocytes from D55 rats were low, relative to control. Chronic (12-day) insulin treatment of D55 rats prevented the rise in heparin-releasable LDL and the reduction in cell-associated LPL activity. Moreover, acute (90-min) treatment of D55 rats with rapid-acting insulin also reduced the heparin-releasable LPL activity to normal levels, although it had no effect on the low cellular LPL activity. When the heparin-releasable LPL pool was allowed to recover for 1 h after removal of the enzyme, D55 rat hearts continued to demonstrate a higher peak LPL activity after a second heparin perfusion. These studies demonstrate that in moderate but not severe diabetes, there is an augmented peak heparin-releasable LPL activity. Whether or not this enhanced heparin-releasable LPL activity has a pathological role in the diabetic heart has yet to be determined.

Lipoprotein lipase (LPL) and cholesteryl ester transfer protein (CETP) are determinants of high-density lipoprotein (HDL) cholesterol concentrations in plasma. We have previously reported that NO-1886, by increasing LPL activity, causes elevation of HDL cholesterol levels in rats. In the present study, we studied the effect of NO-1886 on CETP activity in experimental animals. Since previous reports suggest that rats may lack CETP, we examined hamsters and rabbits, as well as rats. We found that NO-1886 increased LPL activity, resulting in elevation of plasma HDL cholesterol in all three animals. We confirmed that rats lack CETP and that both hamsters and rabbits have high CETP activity. NO-1886 had no effect on CETP activity in hamsters and rabbits. These results demonstrate that the compound NO-1886 elevates HDL cholesterol in experimental animals by selectively increasing LPL activity without any effect on CETP. Animals with low CETP and high LPL activities appear to be more sensitive to NO-1886 than those with high CETP and low LPL activities.

To investigate the implications of endogenous LPL on selective uptake of HDL3-associated cholesteryl esters (HDL3-CEs) by mouse peritoneal macrophages (MPMs), we have performed uptake experiments with MPMs obtained from control mice and transgenic knockout animals expressing LPL exclusively in muscle but not in macrophages. The capacity for HDL3 holoparticle, total HDL3-CE, and selective HDL3-CEs was independent of the expression of functional endogenous LPL (161 vs. 187, 1251 vs. 1300, and 1900 vs. 1113 ng HDL3/mg cell protein; control and LPL-deficient macrophages, respectively). Both control and LPL-deficient macrophages displayed, however, pronounced capacity for total HDL3-CE uptake in excess of HDL3 holoparticle uptake exceeding particle uptake by 7-fold. Despite the fact that endogenous LPL was without any effect on selective uptake, the addition of exogenous LPL led to a significant increase in cellular selective HDL3-CE uptake. Upon addition of purified LPL, HDL3 holoparticle (internalization and degradation), total HDL3-CE, and selective HDL3-CEs, was increased up to 2-fold. HDL3 holoparticle binding to control and LPL-deficient MPMs at 4 degrees C was enhanced 2.7- and 2.6-fold, respectively, in the presence of LPL. The present results suggest that endogenous LPL is without effect on selective uptake of HDL3-CEs. In contrast, the addition of exogenous LPL enhanced selective uptake of HDL3-CEs along with HDL3 holoparticle uptake apparently by the proposed bridging function of the enzyme.

The effect of the apolipoprotein C-II/C-III1 ratio on the capacity of purified bovine milk lipoprotein lipase to hydrolyse triglycerides was measured in a controlled model of pyrene-labeled nonanoyltriglycerides (1-2 ditetradecyl 3-pyrene nonanoyl glyceride) monolayer vesicles. Monolayer was composed of triglycerides, a non-hydrolysable phospholipid ether and cholesterol, a model system where the quality of the interface can be controlled. LPL released fatty acids from pyrene-triglycerides which were transferred from the lipoprotein structure to albumin. This transfer induces a decrease in the excimer production and in the excimer fluorescence intensity. Apolipoprotein C-II and C-III0 and C-III1 were purified from apolipoprotein VLDL. The 2 fragments, C-III1 A (peptide 1-40) and C-III1 B (peptide 41-79), were obtained after thrombin cleavage. Apolipoproteins C-III0 and C-III1 had a similar inhibitory effect on LPL. Inhibition with apo C-III0 or apo C-III1 was 85% of full LPL activity without inhibitor: Apo C-III1 B inhibited 62% of basal activity. It was 27% less effective than apo C-III1. Fragment C-III1 A did not inhibit LPL. The effect of change in both apo C-II (0-0.6 microM) and apo C-III1 (0-1.0 microM) on triglyceride hydrolysis shows the importance of the apo C-II/C-III1 ratio for the release of free fatty acids from triglycerides by LPL. The activating effect of apo C-II in the absence of the apo C-III inhibitor was maximal at 0.06 microM. No further activation was obtained between 0.06 and 0.30 microM. Higher concentrations decreased LPL activity. Apo C-III1 (0.1 microM) decreased the maximum activation by apo C-II from 0.0196 to 0.063 nmol/min/nmol LPL. Higher concentrations of apo C-III1 (0.1-0.5 microM) required higher apo C-II concentrations (0.30 microM instead of 0.06 microM) for maximal activation than when apo C-III1 was absent. The activity of the enzyme without apo C-II was decreased by 65% by 0.12 microM apo C-III1. Increasing the apo C-II/apo C-III1 ratio from 0.1 to 1, increased the activation of the enzyme by a given apo C-II concentration. Moreover, for a given apo C-II/C-III1 ratio, the LPL activation increased with the apo C-II concentration (between 0 and 0.010 microM), until a plateau was reached. This is important, as the change in the C-II/C-III1 ratio is not the only factor affecting LPL activity, and inhibition by apo C-III1 also depends on the overall quantity of apolipoproteins. Extrapolation of these results suggests that hyperlipoproteinemia seems to be more likely due to overproduction of VLDL, than to a decrease in lipoprotein lipase activity.

Objective: To evaluate the impact of chronic inflammation on lipoprotein lipase (LPL) levels and tri-glyceride metabolism in patients wit 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 outpatients at a University Rheumatology clinic. The controls came from the same reference area., Subjects: Altogether 17 consecutive postmenopausal 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 alpha. TNF-alpha: interleukin 1 beta, IL-1 beta: 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 (rs = -0.63, P < 0.05) and C-reactive protein (CRP) (rs = -0.54, P < 0.05) and close to significant for haptoglobin (rs = -0.48, P = 0.087) and IL-6 (rs = -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. Preheparin 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.

This study examined the differences in mechanisms of toxicity when adipose cells from males and females were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Glucose uptake by adipose tissue in vitro was decreased significantly in male guinea pigs within 1 d of intraperitoneal injection of TCDD, but there was no significant effect in females, even at 28 d after treatment. A similar difference between male and female guinea pigs was detected in the effect of TCDD on lipoprotein lipase (LPL) activity, except that a significant decrease in LPL activity was observed 28 d after treatment. Experiments with adipose tissue explants from untreated guinea pigs and macaques revealed similar gender differences in the effect of TCDD in vitro on glucose uptake and LPL activity. Both time-course studies and dose-response studies with TCDD in vitro confirmed the greater sensitivity of male tissues to TCDD toxicity. TCDD induced lipid peroxidation in the adipose tissues of male guinea pigs, while it had no effect in females. 3H-TCDD binding affinity studies in adipose explant tissues showed that tissues from male guinea pigs and monkeys had a higher binding capacity for TCDD than female tissues. TCDD induced a significant reduction in nuclear protein phosphorylation and an increase in cytosolic protein phosphorylation in adipose tissue from male guinea pigs; the effects in female tissues were opposite: nuclear protein phosphorylation increased and cytosolic protein phosphorylation decreased. In a cell-free system in the absence of the nucleus, adipose tissues from male guinea pigs and monkeys responded to TCDD with a rapid stimulation of tyrosine kinase activity but female tissues from both species had a significantly lower and slower response. TCDD induced the DNA binding of AP-1 in adipose tissues of male guinea pigs, but in female tissues TCDD reduced the DNA binding of AP-1. In summary, the results of this study demonstrate gender differences in the response of nonreproductive cells to TCDD. Some of these differences involve different mechanisms of toxicity in both the cytoplasmic and nuclear compartments of the cell.

Lipoprotein lipase (LPL) supplies brown adipose tissue with fatty acids for nonshivering thermogenesis. In brown adipose tissue of the Djungarian hamster we studied i) the molecular mechanisms involved in cold-induced stimulation of LPL activity, ii) the adrenergic control of LPL expression, and iii) compared LPL expression in brown and white adipose tissue. i) After 8 h cold exposure we detected a 2-fold increase in LPL activity and protein level in brown adipose tissue, whereas LPL mRNA level remained unchanged. A cold-induced increase (1.5-fold) in LPL activity was observed in brown adipose tissue of hamsters treated with actinomycin D prior to 4 h cold exposure, whereas cycloheximide treatment completely abolished LPL stimulation. Thus, these data suggest that during the initial phase (< 24 h) of cold exposure the stimulation of LPL activity in brown adipose tissue is most likely due to increased translation. In contrast, during prolonged cold exposure, we detected a maximal 7-fold increase in LPL activity and a 2- to 3-fold increase in LPL mRNA level in brown adipose tissue indicating LPL regulation at the pretranslational level. Furthermore, comparison of LPL protein and activity in brown adipose tissue during prolonged (> 24 h) cold exposure provides some evidence that the active fraction of the enzyme pool in brown adipose tissue is increased in response to cold. ii) Surgical denervation and noradrenaline treatment revealed a complex role of the sympathetic innervation in the control of LPL expression in brown adipose tissue. Denervation decreased LPL mRNA level, but increased LPL activity. Noradrenaline treatment stimulated LPL activity to a similar extent as cold exposure. However, cold-induced stimulation of LPL activity was not impaired by denervation. iii) Cold exposure significantly elevated LPL mRNA content of inguinal white adipose tissue, although LPL activity was not affected. Posttranscriptional mechanisms appear to be involved in the tissue specific control of LPL expression.

The effects of in vivo lipopolysaccharide administration on serum lipid metabolism were studied in normal and hepatoma-bearing rats. Changes in serum lipid levels and adipose tissue lipase (lipoprotein lipase and hormone-sensitive lipase) activities following injection of lipopolysaccharide into normal rats resembled those in hepatoma-bearing rats. These results suggest the presence of some common factor(s) involved in the incidence of abnormal lipid metabolism upon lipopolysaccharide injection and hepatoma transplantation.

Adipose tissue lipoprotein lipase (ATLPL) is responsible for the provision of lipoprotein-derived fatty acids to adipocytes for storage as triglycerides. Fasting ATLPL has been shown to be decreased in non-insulin-dependent diabetes mellitus (NIDDM), an insulin-resistant state. Medically uncomplicated obesity, another state of relative insulin resistance, is associated with decreased stimulation of the enzyme in response to metabolic stimuli. It was therefore hypothesized that the increased insulin resistance of NIDDM would result in an even greater defect in the response of ATLPL to insulin/glucose. Gluteal adipose tissue biopsies were performed in 13 premenopausal obese women with NIDDM, before and after 6 hours of intravenous insulin and glucose. Metabolic data from these studies were then compared with those obtained from 26 nondiabetic obese women of similar age, weight, and fasting insulin concentration (obese controls [OBC]). As expected, fasting gluteal ATLPL activity was lower in the NIDDM group than in OBC (3.7 +/- 0.9 v 11.1 +/- 1.6 nmol free fatty acids [FFA]/min/10(6) cells, P = .0003). The change in ATLPL activity (delta ATLPL) in response to a 6-hour insulin/glucose infusion was not statistically different between the two groups (2.2 +/- 1.1 v 4.7 +/- 1.2, P = .114). However, in NIDDM subjects there was a strong positive relationship between delta ATLPL and glycohemoglobin (GHb) level (r = .883, P = .0001).(ABSTRACT TRUNCATED AT 250 WORDS)

To identify the species differences in lipoprotein hydrolysis, plasma lipoproteins and lipoprotein lipase (LPLase) prepared from both rats and chicks were incubated in vitro in the presence of Triton WR-1339 at concentrations up to 500 micrograms/ml. Rate of lipoprotein hydrolysis by LPLase declined gradually with an increase of Triton concentration irrespective of differences in sources in the lipoprotein and LPLase. At 250 micrograms/ml Triton, the lipoprotein hydrolysis was inhibited by 90% in rats but was only inhibited by < 20% in chicks. Lipoprotein hydrolysis inhibited by Triton was partly recovered by an increase of LPLase concentration, and extents of the recovery were prominent either when rat lipoprotein was provided in place of chick lipoprotein and when rat LPLase rather than chick LPLase was used as the enzyme source for each lipoprotein. These results suggest species differences between chicks and rats with regard to the affinity of Triton to LPLase and lipoprotein and/or the chemical characteristics of both LPLase and lipoprotein.

We evaluated the pharmacokinetics of IV administered sodium heparin and the pharmacodynamic effect of heparin on lipoprotein lipase (LPL) activity. Horses were allotted to 3 groups. Plasma samples were obtained from each horse before and at various times for 6 hours after heparin administration for determination of heparin concentration, LPL activity, and activated partial thromboplastin time (APTT). The disposition of heparin was dose dependent. The area under the plasma heparin concentration vs time curve (AUC) increased more than proportionally with dose, indicating that heparin elimination was nonlinear. Total clearance of heparin was similar after the 40 and 80 IU/kg of body weight dosages, averaging 0.45 and 0.36 IU/kg/min, respectively. However, after administration of the 120 IU/kg dose, clearance was significantly less than that after the 40 IU/kg dose. The half-life of heparin averaged 53, 70, and 136 minutes after 40, 80, and 120 IU/kg, respectively, with significant differences observed between the low and high doses. In contrast to heparin, the area under the plasma concentration vs time curve for LPL activity increased less than proportionally with dose. Maximal LPL activity observed was independent of dose, averaging 4.8 mumol of free fatty acids/ml/h. The APTT was significantly prolonged for 120 minutes after administration of the 40 IU/kg dose. Correlation coefficients for LPL activity vs either plasma heparin concentration or APTT were less than 0.7, indicating that neither laboratory measure can be used to accurately predict plasma LPL activity.