Higher Lipoprotein Lipase Activity Research Articles

Abstract 15518: The Effects of High Glucose and Lipoprotein Lipase on Macrophage Regulatory Function

Introduction: Atherosclerosis has an established inflammatory, macrophage(MФ)-mediated component which can be exacerbated by uncontrolled diabetes. However, there are also protective, regulatory MФ processes that can help quell atherosclerosis. Lipoprotein Lipase (LPL) on the MФ surface hydrolyzes circulating triglyceride-rich lipoproteins into glycerol and free fatty acids to provide a non-glucose energy source. Hypothesis: We hypothesized that regulatory MФs have high LPL activity, which could promote fatty acid metabolism to drive inflammation-resolving functions, and that this LPL activity is inhibited by ambient glucose. Methods and Results: MФs were cultured and differentiated from bone marrow harvested from wild-type mice aged 9-16 weeks. Two weeks after harvest, these MФs were polarized with (1) interferon-γ and lipopolysaccharide to stimulate classically-activated, inflammatory MФs or (2) interleukin-4 to stimulate alternatively-activated, regulatory MФs. The resulting phenotypes were validated by canonical transcript markers (Tnfa/Nos2 for inflammatory MФs and Ym1/Arg1 for regulatory MФs) and cell surface markers (CD86 and CD206, respectively). Using a triglyceride analog that fluoresces when cleaved by LPL, we found that regulatory MФs have far greater LPL activity than inflammatory macrophages at baseline (33 ± 2 vs 1 ± 0.2 a.u., p < 0.001, n=8). By varying glucose concentration during the polarization, this effect was most pronounced at normal, physiological concentrations of glucose (5 mM, ~90 mg/dL) and blunted at a high-glucose concentration that can be found in uncontrolled diabetes (25 mM). We also report on lipoxygenase expression and specialized pro-resolving mediator production as effector functions downstream of LPL activity in regulatory MФs. Conclusions: Taken together, our findings support a model in which regulatory MФs are programmed to utilize LPL to drive the inflammation-resolving phenotype and that this process works best at low, physiologic glucose concentrations. Future translational work will investigate whether a lack of LPL-mediated regulatory MФ function is a reason why patients with uncontrolled diabetes have higher atherosclerotic burden and plaque instability.

Abstract 14344: The Competing Roles of Glucose and Lipoprotein Lipase on Regulatory Macrophage Function

Background: Atherosclerosis causes more death than any other pathophysiologic process. It has a well-established inflammatory, macrophage(MФ)-mediated component which can be stoked by uncontrolled diabetes. However, there are also protective, regulatory MФ processes that can help quell atherosclerosis. Lipoprotein Lipase (LPL) on the MФ surface can hydrolyze circulating triglyceride-rich lipoproteins into glycerol and free fatty acids to provide a non-glucose energy source. We hypothesized that regulatory MФs have high LPL activity, which would promote fatty acid metabolism to drive inflammation-resolving functions, and that this LPL activity is inversely related to ambient glucose. Results: MФs were cultured and differentiated from bone marrow harvested from wild-type mice aged 9-16 weeks. Two weeks after harvest, these MФs were polarized with (1) interferon-γ and lipopolysaccharide to stimulate classically-activated, inflammatory MФs or (2) interleukin-4 to stimulate alternatively-activated, regulatory MФs. The resulting phenotypes were validated by canonical transcript markers ( Tnfa / Nos2 for inflammatory MФs and Ym1 / Arg1 for regulatory MФs) and cell surface markers (CD86 and CD206, respectively). Using a triglyceride analog that fluoresces when cleaved by LPL, we found that regulatory MФs have far greater LPL activity than inflammatory macrophages at baseline (33 ± 2 vs 1 ± 0.2 a.u., p < 0.001, n=8). By varying glucose concentration during the polarization, this effect was most pronounced at normal, physiological concentrations of glucose (5 mM, ~90 mg/dL) and blunted at a high-glucose concentration that can be found in uncontrolled diabetes (25 mM). Each experiment was repeated across multiple batches of MФs (n≥4) and from multiple mice (n=15), male and female. Conclusions: Taken together, our findings support a model in which regulatory MФs are programmed to utilize LPL to drive the inflammation-resolving phenotype and that this process works best at low, physiologic glucose concentrations. Future translational work will investigate whether a lack of LPL-mediated regulatory MФ function is a reason why patients with uncontrolled diabetes have higher atherosclerotic burden and plaque instability.

Human apolipoprotein A-II reduces atherosclerosis in knock-in rabbits

Background and aimsApolipoprotein A-II (apoAII) is the second major apolipoprotein of the high-density lipoprotein (HDL) particle, after apoAI. Unlike apoAI, the biological and physiological functions of apoAII are unclear. We aimed to gain insight into the specific roles of apoAII in lipoprotein metabolism and atherosclerosis using a novel rabbit model. MethodsWild-type (WT) rabbits are naturally deficient in apoAII, thus their HDL contains only apoAI. Using TALEN technology, we replaced the endogenous apoAI in rabbits through knock-in (KI) of human apoAII. The newly generated apoAII KI rabbits were used to study the specific function of apoAII, independent of apoAI. ResultsApoAII KI rabbits expressed exclusively apoAII without apoAI, as confirmed by RT-PCR and Western blotting. On a standard diet, the KI rabbits exhibited lower plasma triglycerides (TG, 52%, p < 0.01) due to accelerated clearance of TG-rich particles and higher lipoprotein lipase activity than the WT littermates. ApoAII KI rabbits also had higher plasma HDL-C (28%, p < 0.05) and their HDL was rich in apoE, apoAIV, and apoAV. When fed a cholesterol-rich diet for 16 weeks, apoAII KI rabbits were resistant to diet-induced hypertriglyceridemia and developed significantly less aortic atherosclerosis compared to WT rabbits. HDL isolated from rabbits with apoAII KI had similar cholesterol efflux capacity and anti-inflammatory effects as HDL isolated from the WT rabbits. ConclusionsApoAII KI rabbits developed less atherosclerosis than WT rabbits, possibly through increased plasma HDL-C, reduced TG and atherogenic lipoproteins. These results suggest that apoAII may serve as a potential target for the treatment of atherosclerosis.

ANGPTL8 has both endocrine and autocrine effects on substrate utilization.

The angiopoietin-like protein ANGPTL8 (A8) is one of 3 ANGPTLs (A8, A3, A4) that coordinate changes in triglyceride (TG) delivery to tissues by inhibiting lipoprotein lipase (LPL), an enzyme that hydrolyzes TG. Previously we showed that A8, which is expressed in liver and adipose tissue, is required to redirect dietary TG from oxidative to storage tissues following food intake. Here we show that A8 from liver and adipose tissue have different roles in this process. Mice lacking hepatic A8 have no circulating A8, high intravascular LPL activity, low plasma TG levels, and evidence of decreased delivery of dietary lipids to adipose tissue. In contrast, mice lacking A8 in adipose tissue have higher postprandial TG levels and similar intravascular LPL activity and plasma A8 levels and higher levels of plasma TG. Expression of A8, together with A4, in cultured cells reduced A4 secretion and A4-mediated LPL inhibition. Thus, hepatic A8 (with A3) acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues, whereas A8 in adipose tissue enhances LPL activity by autocrine/paracrine inhibition of A4. These combined actions of A8 ensure that TG stores are rapidly replenished and sufficient energy is available until the next meal.

Increased plasma lipoprotein lipase activity in males with autism spectrum disorder

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with complex genetics, characterized by impaired social communication and repetitive behaviors and interests. The involvement of lipid metabolism in ASD pathophysiology has been demonstrated in previous studies; however, the molecular mechanisms of abnormal lipid metabolism are not fully understood. A mutation in Lipoprotein lipase (LPL), which has central roles in lipid metabolism, has been identified in patients with ASD. We have reported that Lpl is downregulated in ASD model mice. Therefore, we explored the role of LPL in lipid metabolism in ASD patients. MethodsWe quantified LPL amount, LPL activity, and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) amount in the plasma of ASD male subjects (n = 28) compared with typical development (TD) controls (n = 28), using enzyme-linked immunosorbent assay for LPL amount and fluorometric assays for LPL activity. We examined the correlations of plasma LPL with GPIHBP1 and clinical characteristic scores from the Autism Diagnostic Interview-Revised (ADI-R). ResultsThere was higher LPL activity, but not LPL amount, in the plasma of ASD subjects compared with controls. Receiver operating characteristics analysis also demonstrated that pure LPL activity (LPL activity/LPL amount) is a useful indicator to distinguish ASD from TD controls. There were no correlations between plasma LPL and ADI-R scores; however, LPL activity was negatively correlated with GPIHBP1 levels in the plasma of ASD subjects. ConclusionsOur results demonstrate increased activity of plasma LPL, regulated by GPIHBP1, in ASD, providing novel insights into the lipid metabolism associated with ASD pathophysiology.

Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 and angiopoietin-like protein 4 are associated with the increase of lipoprotein lipase activity in epicardial adipose tissue from diabetic patients

Background and aimsEpicardial adipose tissue (EAT) is a visceral AT, surrounding myocardium and coronary arteries. Its volume is higher in Type 2 diabetic (DM2) patients, associated with cardiovascular disease risk. Lipoprotein lipase (LPL) hydrolyses triglycerides (TG) from circulating lipoproteins, supplying fatty acids to AT, contributing to its expansion. We aimed to evaluate LPL expression and activity in EAT from DM2 and no DM2 patients, and its regulators ANGPTL4, GPIHBP1 and PPARγ levels, together with VLDLR expression and EAT LPL association with VLDL characteristics. MethodsWe studied patients undergoing coronary by-pass graft (CABG) divided into CABG-DM2 (n = 21) and CABG-noDM2 (n = 29), and patients without CABG (No CABG, n = 30). During surgery, EAT and subcutaneous AT (SAT) were obtained, in which LPL activity, gene and protein expression, its regulators and VLDLR protein levels were determined. Isolated circulating VLDLs were characterized. ResultsEAT LPL activity was higher in CABG-DM2 compared to CABG-noDM2 and No CABG (p=0.002 and p<0.001) and in CABG-noDM2 compared to No CABG (p=0.02), without differences in its expression. ANGPTL4 levels were higher in EAT from No CABG compared to CABG-DM2 and CABG-noDM2 (p<0.001). GPIHBP1 levels were higher in EAT from CABG-DM2 and CABG-noDM2 compared to No CABG (p= 0.04). EAT from CABG-DM2 presented higher PPARγ levels than CABG-noDM2 and No CABG (p=0.02 and p=0.03). No differences were observed in VLDL composition between groups, although EAT LPL activity was inversely associated with VLDL-TG and TG/protein index (p<0.05). ConclusionsEAT LPL regulation would be mainly post-translational. The higher LPL activity in DM2 could be partly responsible for the increase in EAT volume.

Distinct metabolic pathways trigger adipocyte fat accumulation induced by high-carbohydrate and high-fat diets

ObjectiveSeveral metabolic pathways may be associated with obesity development and may be differentially modulated by dietary constituents. The aim of this study was to access the adipocyte metabolic pathways that lead to lipid accumulation in fat cells of mice fed a high-carbohydrate or high-fat diet. MethodsMale Swiss mice ages 7 to 8 wk were fed a standard laboratory rodent diet—chow diet, a high-carbohydrate (HC) diet, or a high-fat (HF) diet for 8 wk. ResultsAnimals fed the HC diet exhibited a high lipogenesis rate and lipoprotein lipase activity even in a fasted state. Peroxisome proliferator-activated receptor gamma and sterol regulatory element-binding proteins-1 mRNAs were increased in adipose tissue. The HF diet did not promote the lipogenic pathways but attenuated lipolytic activity and glucose uptake in adipocytes. ConclusionThe HC diet induces constitutive expression of lipogenic transcription factors during fasting, whereas the HF diet decreases lipolysis in adipocytes. Both pathways may contribute to increase fat stores and maintain an obese state.

Lipoprotein lipase in non-small cell lung cancer tissue is highly expressed in a subpopulation of tumor-associated macrophages

High lipoprotein lipase (LPL) activity in non-small cell lung cancer (NSCLC) tissue strongly predicts shorter patient survival. We tested the hypothesis that in NSCLC tissue, macrophages are the major site of LPL expression. LPL expression in the entire NSCLC tissue and in the adjacent non-cancer lung tissue was compared to the expression of genes preferentially expressed in macrophages. LPL expression at the cellular level was analyzed by mRNA fluorescence in situ hybridization. In the whole cancer tissue (but not in the adjacent non-cancer tissue), expression of LPL correlated with expression of genes preferentially expressed in macrophages (MSR1, CD163, FOLR2), but not with expression of genes preferentially expressed in tumor cells. All cells in the cancer and adjacent non-cancer tissue exhibit low LPL expression. However, in cancer tissue only, there were individual highly LPL-expressing cells which were macrophages. These LPL-overexpressing cells were approximately 10 times less abundant than anti-CD163-stained, tumor-associated macrophages. To conclude, in NSCLC tissue, a subpopulation of tumor-associated macrophages highly expresses LPL. Because tumor-associated macrophages are pro-tumorigenic, these cells should be further characterized to better understand the underlying nature of the close relationship between high LPL activity in NSCLC tissue and shorter patient survival.

Over-Expression of Human Lipoprotein Lipase in Mouse Mammary Glands Leads to Reduction of Milk Triglyceride and Delayed Growth of Suckling Pups

BackgroundThe mammary gland is a conserved site of lipoprotein lipase expression across species and lipoprotein lipase attachment to the luminal surface of mammary gland vascular endothelial cells has been implicated in the direction of circulating triglycerides into milk synthesis during lactation.Principal FindingsHere we report generation of transgenic mice harboring a human lipoprotein lipase gene driven by a mammary gland-specific promoter. Lipoprotein lipase levels in transgenic milk was raised to 0.16 mg/ml, corresponding to an activity of 8772.95 mU/ml. High lipoprotein lipase activity led to a significant reduction of triglyceride concentration in milk, but other components were largely unchanged. Normal pups fed with transgenic milk showed inferior growth performances compared to those fed with normal milk.ConclusionOur study suggests a possibility to reduce the triglyceride content of cow milk using transgenic technology.

Is there a relationship between the kinetics of lipoprotein lipase activity after a meal and the susceptibility to hepatic steatosis development in ducks?

The difference in the ability of Pekin and Muscovy ducks to develop hepatic steatosis could result from a different peripheral lipoprotein lipase (LPL) activity, which hydrolyses triacylglycerol secreted by the liver. We studied the kinetics of plasma LPL activity in response to a meal at different ages in Pekin and Muscovy ducks. For that purpose, blood samples were taken at 5, 9, 12, 13, and 14 wk of age just before and 1, 2, 4, and 8 h after a meal. To release LPL into general circulation, an i.v. injection of heparin (400 IU/kg of BW) was administered 10 min before blood collection. For that reason, different ducks per genotype were used for each point of measurement (n = 6). Plasma LPL activity measured before the meal was negatively correlated with the weight of the fatty liver measured in the same ducks at 14 wk of age (r = -0.58, P < 0.001). Plasma triacylglycerol level measured before the meal was negatively correlated with plasma LPL activity measured in the same ducks (r = -0.31, P = 0.025) and was negatively correlated with plasma LPL activity measured in the same ducks for each age and each timing (r = -0.39, P < 0.001). At 14 wk of age for Muscovy and Pekin ducks, we observed that a high plasma LPL activity (>200 IU/L of plasma) corresponded to a relatively low development of fatty liver (190 g) induced by overfeeding, whereas a low plasma LPL activity (<150 IU/L of plasma) corresponded to a high propensity to develop fatty liver (470 g). In conclusion, plasma LPL activity measured just before the meal during the rearing period could be used as a marker of hepatic steatosis development during the overfeeding period.

Increased Fatty Acid Synthase Activity in Non-small Cell Lung Cancer Tissue Is a Weaker Predictor of Shorter Patient Survival than Increased Lipoprotein Lipase Activity

Cumulative evidence suggests the involvement of fatty acid synthase (FAS) in tumor growth. We tested the hypothesis that increased FAS activity and gene expression in non-small cell lung cancer (NSCLC) tissue have a prognostic significance that is independent of that of increased lipoprotein lipase (LPL) activity in the same tissue. Forty two consecutive patients with resected NSCLC were enrolled in the study. Paired samples of lung cancer tissue and adjacent non-cancer lung tissue were collected from resected specimens for estimation of FAS activity and expression of its gene. LPL activity had previously been measured in the same tissues. During a 4-year follow-up, 21 patients died due to tumor progression. One patient died due to a non-cancer reason and was not included in the analysis. High FAS activity in cancerous tissue relative to that in the adjacent non-cancer lung tissue was associated with weight loss in the 3 months immediately before tumor excision and patient death during the follow-up. Higher FAS activity in the cancer tissue was associated with higher LPL activity in the same tissue, which also predicted shorter patient survival, but LPL was the stronger predictor. FAS gene expression was higher in the adjacent non-cancer tissue than in the cancer tissue but had no predictive value. Our study further underlines the involvement of cancer tissue FAS activity in tumor growth but also indicates its weaker importance compared to LPL activity.

Lipoprotein lipase and premature coronary artery disease

Objective— This study investigates the relationship between post-heparin plasma lipoprotein lipase (LPL) activity, chronic inflammation and premature stable coronary artery disease (CAD) in male patients.Methods and results— 132male patients (<55years) with documented stable CAD (cases) and 130male subjects without CAD were enrolled. Cases had higher values of high-sensitivity C-reactive protein (hs-CRP) and lower LPL activity [(5.31±3.06) mg/l vs. (2.67±1.01) mg/l, P<0.01; (27.39±6.71) nmol•ml-1•min-1 vs. (37.06±7.22) nmol•ml-1•min-1, P<0.01, respectively]. LPL activity was inversely associated with hs-CRP and triglycerides (TG), and positively associated with HDL-C (r = -0.761, P<0.001; r = -0.339, P<0.001; r=0.217, P<0.05; respectively) in cases. In multivariate analysis, higher values of hs-CRP (OR 1.45, 95% CI: 1.083~1.951; P=0.013), BMI, LDL-C and hypertension were significant predictors of premature stable CAD in male patients. Higher LPL activity decreases risk of premature stable CAD (OR 0.87, 95% CI: 0.809~0.933; P=0.000). LPL activities decreased with the increased number of significantly stenosed vessels (P<0.05).Conclusions— LPL activity and hs-CRP are significant predictors of premature stable CAD in male patients and are inversely correlated.

Influence of lipoprotein-lipase activity on plasma triacylglycerol concentration and lipid storage in three genotypes of ducks

The lipoprotein-lipase (LPL) hydrolyses the triacylglycerols (TG) secreted by the liver and, thus, allows the storage of lipids onto the extrahepatic tissues. The LPL activity has been studied by injection of LPL antibodies in three genotypes of ducks (Muscovy ( Cairina moschat), Pekin ( Anas plathyrhynchos) and Mule (hybrids of male Muscovy ducks and female Pekin ducks)) under overfeeding condition. The results show a similar weight gain between injected and control animals. A higher liver steatosis is observed in Mule ducks (616 ± 18 g; 8.79% of body mass (BW)) and Muscovy ducks (514 ± 13 g; 7.05% BW) compared to Pekin ducks (353 ± 21 g; 5.89% BW, p < 0.05). Pekin ducks showed a much marked extrahepatic fattening of abdominal and subcutaneous adipose tissues. The LPL activity was evaluated by comparing the evolution of the plasma TG concentrations after injections of saline (control animals) or injections of specific LPL-antibodies. Inhibition of LPL activity performed by intravenous injections of LPL-antibodies showed a spectacular increase in the plasma TG concentrations in the three genotypes. That increase was considerably higher in Pekin ducks (98 ± 10 g/L) compared to Muscovy ducks (35 ± 2 g/L, p < 0.01) and Mule ducks (30 ± 4 g/L, p < 0.01). Those data suggest that a high export of lipids synthesized in liver and a high LPL activity occur in overfed Pekin ducks, which can favour the extrahepatic fattening to the detriment of the liver steatosis, and conversely in overfed Muscovy and Mule ducks.

Removal of triacylglycerols from chylomicrons and VLDL by capillary beds: the basis of lipoprotein remnant formation

The triacylglycerol content of chylomicrons and VLDL (very-low-density lipoprotein) compete for the same lipolytic pathway in the capillary beds. Although chylomicron triacylglycerols appear to be the favoured substrate for lipoprotein lipase, VLDL particles compete in numbers. Methods to quantify the specific triacylglycerol removal from VLDL and chylomicrons may involve endogenous labelling of the triacylglycerol substrate with stable isotopes in combination with arteriovenous blood sampling in humans. Arteriovenous quantification of remnant lipoproteins suggests that adipose tissue with its high lipoprotein lipase activity is a principal site for generation of remnant lipoproteins. Under circumstances of reduced efficiency in the removal of triacylglycerols from lipoproteins, there is accumulation of remnant lipoproteins, which are potentially atherogenic.

LIPOPROTEIN LIPASE ACTIVITY AND GENE EXPRESSION IN LUNG CANCER AND IN ADJACENT NONCANCER LUNG TISSUE

The authors tested the hypothesis that lipoprotein lipase (LPL) gene expression and enzyme activity are increased in lung cancer tissue, as compared to adjacent, apparently healthy, lung tissue. Paired samples of lung cancer tissue and adjacent noncancer lung tissue were collected from 42 patients with resectable non-small cell lung cancer. LPL activity was higher in cancer tissue (1.9-fold median difference, P < .0001); however, LPL gene expression was higher in noncancer tissue (3.8-fold median difference, P < .0001). The higher LPL activity in lung cancer tissue provides a possible mechanism for increasing the supply of lipid nutrients to the tumor, necessary for tumor growth.

Regional Differences in Adipose Tissue Metabolism in Women

Studies comparing adipose tissue metabolism in central versus peripheral fat depots have generated equivocal data. We examined whether regional differences in abdominal subcutaneous and omental adipose tissue metabolism in women exist and whether they persist across the spectrum of body fatness and abdominal adiposity values. We measured adipocyte size; lipoprotein lipase (LPL) activity; and basal, isoproterenol-, forskolin-, and dibutyryl cAMP-stimulated lipolysis in adipose tissue or mature adipocytes isolated from the omental and subcutaneous fat depots in a sample of 55 healthy women undergoing elective gynecological surgery. Measures of body fat mass and body fat distribution were also obtained by dual-energy X-ray absorptiometry and computed tomography. Subcutaneous adipocytes were significantly larger than omental adipocytes (P < 0.0001). LPL activity expressed as a function of cell number was significantly higher in subcutaneous versus omental adipose tissue (P < 0.0001). Basal, isoproterenol-stimulated, dibutyryl cAMP-stimulated (10(-3) mol/l) and forskolin-stimulated (10(-5) mol/l) lipolysis (expressed as a function of cell number) were all significantly higher in subcutaneous versus omental adipocytes (P < 0.05 to P < 0.0001). However, the response of omental adipocytes to lipolytic stimuli tested (fold increase over basal level) was significantly greater in magnitude compared with subcutaneous adipocytes (P < 0.01). These differences were relatively constant across total body fat mass and visceral adipose tissue area tertiles. In conclusion, compared with adipocytes from the omental fat compartment, subcutaneous adipocytes are larger, have higher LPL activity, and are more lipolytic on an absolute basis, which may reflect a higher fat storage capacity in this depot in women. In contrast, omental adipocytes display greater relative responsiveness to both adrenergic receptor-and postreceptor-acting agents compared with subcutaneous adipocytes. Overall and visceral obesity have only minor effects on regional differences in adipose tissue metabolism.

High lipoprotein lipase activity increases insulin sensitivity in transgenic rabbits

Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of triglyceride-rich lipoproteins and plays an important role in glucose metabolism. To examine the hypothesis that increased LPL activity may alter insulin sensitivity, we investigated glucose metabolism and insulin sensitivity in transgenic (Tg) rabbits expressing the human LPL gene under the control of a β-actin promoter. An intravenous glucose tolerance test showed that the plasma glucose clearance rate was not significantly different between Tg and non-Tg rabbits; however, the area under the curve for insulin and free fatty acids in Tg rabbits was significantly reduced compared with that of non-Tg rabbits ( P < .05). Using the intravenous insulin tolerance test, we found that the area of under the curve of glucose of Tg rabbits was also significantly reduced ( P < .01). Furthermore, euglycemic-hyperinsulinemic clamp test revealed that the mean glucose infusion rate in Tg rabbits was significantly higher than in non-Tg rabbits ( P < .05). These results demonstrate that systemic overexpression of LPL increases whole-body insulin sensitivity and genetic manipulation of LPL genes may be a potential target for the treatment of diabetic patients.

Nicotinic Acid Increases Lipoprotein Lipase Activity in Skeletal Muscle, But Only When Sedentary

1015 Nicotinic acid treatment (niacin) is known to reduce coronary heart disease and all cause mortality. An important mechanism thought to be mediating the cardioprotective effect of niacin is the marked lowering of plasma triglyceride rich lipoproteins and the elevation of high density lipoprotein concentrations. Because skeletal muscle lipoprotein lipase (LPL) is a key enzyme is the catabolism of plasma triglycerides and plays an important role in HDL metabolism, niacin may be mediating some of its effects on lipoprotein metabolism via LPL regulation. PURPOSE: The purpose of this study was to determine if nicotinic acid affects muscle LPL activity. METHODS: As muscle LPL regulation is highly dependent upon recent contractile activity (Bey and Hamilton, J.Physiol. 551, 2003), we tested the effect of nicotinic acid on muscle LPL in 3–4 month old female ambulatory rats that have normally high muscle LPL activity and in these rats when the skeletal muscle was made physically inactive for 11 hours by hindlimb unloading. Nicotinic acid plus saline or saline alone was infused i.p. throughout the 11 hours in both ambulatory and hindlimb unloaded rats. After 11 hours, rats were anesthetized and soleus and red gastrocnemius (RG) muscles were harvested and analyzed for heparin releasable LPL (HR-LPL) activity. RESULTS: In agreement with our recent findings, physical inactivity markedly reduced soleus and RG HR-LPL activity by 89 and 90%, respectively (both p < 0.01), compared to ambulatory levels. The treatment of ambulatory healthy rats with nicotinic acid did not affect HR-LPL activity in either soleus or RG. Remarkably, nicotinic acid treatment of hindlimb unloaded rats resulted in 9 and 7 fold greater soleus and RG HR-LPL activity, respectively, than treatment with saline alone (both p < 0.01). Therefore, nicotinic acid completely restored soleus HR-LPL activity to 100% of ambulatory rat levels and partially restored RG to 68% of HR-LPL activity in ambulatory rats. CONCLUSIONS: Nicotinic acid can have a marked effect on skeletal muscle LPL regulation, presumably through reduction of adipose tissue lipolysis, and this ability is very dependent on recent contractile activity. Supported by NIH HL70482-01.

A paradox resolved: the postprandial model of insulin resistance explains why gynoid adiposity appears to be protective

Although an increased visceral adipose mass is clearly linked to insulin resistance syndrome and increased vascular risk, some studies suggest that the ratio of visceral to subcutaneous fat (gynoid or abdominal) is a better correlate of insulin resistance. For example, the utility of waist-to-hip ratio as a risk factor illustrates this principle – and suggests that gynoid obesity may somehow be protective. The postprandial model of insulin resistance – the hypothesis that excessive postprandial free, fatty acid (FFA) flux plays a key role in the genesis of the insulin resistance syndrome – may help to rationalize this seemingly paradoxical observation. A high proportion of this FFA flux is derived, not from adipocytes, but from meal-derived fatty acids that adipocytes fail to store following chylomicron breakdown; insulin-resistant adipocytes are notably inefficient in regard to FFA storage. Hypertrophied visceral adipocytes are poorly insulin sensitive, whereas gynoid adipocytes tend to be highly insulin sensitive. After a fatty meal, the lipoprotein lipase (LPL) activities associated with the various depots – visceral and subcutaneous adipocytes, as well as skeletal muscle – effectively compete to hydrolyze chylomicra. When circulating triglycerides are broken down by muscle or by insulin-sensitive subcutaneous adipocytes, the evolved fatty acids are apt to be stored immediately – whereas the fatty acids produced by chylomicron breakdown in the visceral depot are much more prone to escape to the circulation and contribute to high postprandial FFA flux. Thus, the LPL activity of gynoid adipocytes provides protection from the potentially adverse metabolic consequences of fatty meals – and a large mass of gynoid adipocytes presumably is a marker for high LPL activity in this depot. The ability of the postprandial model of insulin resistance to rationalize the seeming protection afforded by gynoid obesity constitutes evidence that this model has validity.

Activity and concentration of lipoprotein lipase in post-heparin plasma and the extent of coronary artery disease

Numerous studies have found polymorphisms in the lipoprotein lipase (LPL) gene to be associated with the risk of coronary artery disease (CAD), implicating LPL in the development of atherothrombotic disease. It remains controversial, however, whether LPL acts in a pro- or anti-atherogenic fashion. We quantitated activity and concentration of LPL in post-heparin plasma from 194 male patients undergoing coronary angiography. HDL cholesterol was significantly associated with LPL activity quartiles (1.09±0.26 the highest vs. 0.96±0.25 mmol/l the lowest quartile, P<0.01). There was also a trend towards higher total (5.61±1.33 vs. 5.16±1.44 mmol/l, P=0.059) and LDL cholesterol (3.92±1.39 vs. 3.46±1.06 mmol/l, P=0.09) with higher LPL activity. In contrast, measures of CAD extent showed no differences between LPL quartiles ( P>0.30 for prior myocardial infarction, number of diseased vessels, Gensini and extent scores). Additionally, there was no difference in LPL activity (CAD: n=158, 168±70 nmol/ml/min, no CAD: n=36, 180±89 nmol/ml/min, P=0.47) or concentration (280±121 ng/ml and 288±111 ng/ml, P=0.72) between patients with and without CAD. Our data show that, in spite of an association with lipoprotein parameters, LPL in post-heparin plasma is unrelated to the presence or the extent of CAD. Therefore, lipoprotein lipase determination in plasma does not appear to be a useful marker in the assessment of CAD risk.