Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.34 (lipoprotein lipase)
7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since evidence has appeared that tumor necrosis factor-alpha (TNF) is involved in the loss of body fat in the course of wasting diseases, a large number of studies have investigated the physiological role of this cytokine in adipose tissue. TNF treatment of several in vitro models of adipogenesis clearly showed that TNF is a potent inhibitor of adipose differentiation. This antiadipogenic property is accompanied by suppression of developmental and metabolic markers of fat cell differentiation, such as peroxisome proliferator-activated receptor (PPAR)-gamma2, lipoprotein lipase (LPL), glycerol-3-phosphate dehydrogenase (GPDH) and GLUT4. Moreover, TNF promotes lipolysis in mature adipocytes and, subsequently, a reversion of the adipocyte phenotype. Recent studies demonstrated that TNF directly interferes with the insulin signaling cascade at early steps and, thus, impairs insulin-stimulated glucose transport. Further progress in understanding the role of TNF in adipose tissue was made when endogenous TNF mRNA expression was demonstrated in adipose tissue. Obesity was found to represent a state of overexpression of the TNF system. Such findings support the hypothesis that TNF is a mediator of obesity-linked insulin resistance. However, this concept is mainly based on animal data and is so far only partially supported by studies in humans. Taken together, the results of a variety of experimental and clinical studies suggest that TNF may act as an important auto/paracrine regulator of fat cell function which serves to limit adipose tissue expansion, probably by inducing insulin resistance which may in turn cause metabolic disturbances. Elucidation of the molecular mechanisms of TNF production and action in adipose tissue may help to find new approaches for the treatment of insulin resistance in humans.
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PMID:The role of TNF-alpha in human adipose tissue: prevention of weight gain at the expense of insulin resistance? 1066 12

We developed a strictly controlled serum-free culture system and tested the effects of adipogenic and antiadipogenic agents on the proliferation and(or) adipose conversion of porcine stromal-vascular cells. To avoid any interference with serum components, stromal-vascular cells were isolated, plated, and grown in absence of serum. In these culture conditions, a very limited growth phase and the absence of cell confluence were observed. However, when compared with continuous culture in serum-containing medium, the serum-free conditions were significantly more adipogenic as assessed by increased lipid content and increased enzymatic activities for lipoprotein lipase, glycerol 3-phosphate dehydrogenase, and malic enzyme. In serum-free medium, physiological concentrations of insulin or IGF-I were sufficient to significantly increase the percentage of lipid-containing cells, whereas triiodothyronine (T3) and GH had no effect. Insulin, IGF-I, and, more moderately, T3 also accelerated the lipid filling in the lipid-containing cells. In the presence of insulin, stimulation by T3 or hydrocortisone alone had no effect on glycerol 3-phosphate dehydrogenase activity, whereas their concomitant addition significantly increased it. Chronic exposure to tumor necrosis factor-alpha dose-dependently stimulated cell proliferation but clearly inhibited differentiation. Epidermal growth factor, another known antiadipogenic agent, also significantly increased the proliferation of stromal-vascular cells, but, surprisingly, this was not correlated with inhibition of adipocyte differentiation. Indeed, epidermal growth factor treatment did not decrease lipid filling and significantly improved lipoprotein lipase and malic enzyme activities. Taken together, the results obtained in these strictly controlled serum-free culture conditions point out functions for insulin, IGF-I, hydrocortisone, and T3 during early and(or) later steps of porcine adipose conversion. In addition, this study reports a positive activity of epidermal growth factor on porcine adipocyte differentiation that is in clear contrast with previous works performed with rodent cells.
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PMID:Culture of porcine stromal-vascular cells in serum-free medium: differential action of various hormonal agents on adipose conversion. 1078 78

Atherosclerosis is the major complication of diabetes. Accumulating evidence indicates that lipoprotein lipase (LPL) produced by macrophages in the vascular wall may favor the development of atherosclerosis by promoting lipid accumulation within the lesion. We previously demonstrated that high glucose stimulates in vitro murine and human macrophage LPL production. In this study, we measured macrophage LPL mRNA expression, immunoreactive mass, and activity in normotriglyceridemic subjects with type 2 diabetes. Monocytes isolated from healthy control subjects and patients with type 2 diabetes were differentiated into macrophages in RPMI medium containing 20% autologous serum. After 5 days in culture, macrophage LPL mRNA expression, mass, and activity were determined. Macrophages of diabetic patients cultured in their own sera showed a significant increase in LPL mRNA levels, mass, and activity compared with macrophages of control subjects. Differentiation of macrophages of diabetic patients in sera obtained from control subjects significantly reduced these anomalies. Conversely, culturing macrophages of control subjects in sera of diabetic patients significantly increased LPL mass and activity in these cells. Besides LPL overproduction, macrophages of diabetic patients exhibited an increase in basal and LPL-induced tumor necrosis factor (TNF)-alpha release. TNF-alpha alterations were reduced by exposing these cells to sera of control subjects. Overall, these data demonstrate that macrophages of diabetic patients overexpress LPL and TNF-alpha and that peripheral factors dysregulated in diabetes are, at least in part, responsible for these alterations.
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PMID:Upregulation of macrophage lipoprotein lipase in patients with type 2 diabetes: role of peripheral factors. 1087 Nov 97

Postprandial hyperlipidemia is frequently accompanied with intra-abdominal visceral accumulation in human subjects. We have found that the decreased lipoprotein lipase (LPL) mass and activity is negatively associated with the amount of visceral fat accumulation. Here, we studied the postprandial hyperlipidemia using the OLETF rat, a model with visceral obesity, in order to clarify the molecular mechanism causing postprandial hyperlipidemia accompanied with visceral obesity. At the same age of 32 weeks, the OLETF rats showed obviously higher plasma leptin, total cholesterol, triglyceride, and HDL-cholesterol levels than the control LETO rats, although the plasma glucose level was not significantly different. Fat-loading test revealed the delayed metabolism of exogenous fat in the OLETF rats compared to the LETO rats, similar to human subjects with visceral obesity. In the obese rats, plasma levels of LPL mass and activities were 60 and 49% of control rats. The expression of LPL gene was decreased in subcutaneous adipose tissues and skeletal muscle of OLETF rats to 40 and 52% compared to those of LETO rats. In OLETF rats, plasma tumor necrosis factor-alpha (TNF-alpha) and insulin levels were increased to 2.0- and 2.3-folds compared to those in control rats. Furthermore, plasma insulin and TNF-alpha levels in OLETF rats were negatively correlated with the expression levels of LPL gene in subcutaneous fat and muscle. These results indicate that decreased LPL mass and activity in the animal model with visceral obesity is possibly caused by decreased expression of LPL gene in tissues mediated by the increased levels of insulin and TNF-alpha. The different expression of LPL gene in tissues associated with the increased levels of insulin and TNF-alpha possibly elucidate the underlying mechanisms involving the postprandial hyperlipidemia observed in visceral obesity.
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PMID:Differential expression of lipoprotein lipase gene in tissues of the rat model with visceral obesity and postprandial hyperlipidemia. 1103 39

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is found throughout the environment in industrialized countries, and most people have had some exposure. TCDD has very high lipid solubility and is concentrated in adipose tissue. Because an epidemiologic association between TCDD exposure and diabetes has been described, we examined the effects of TCDD in adipocytes. The addition of TCDD to 3T3-F442a cells, both at the initiation of differentiation and after cells were fully differentiated, resulted in a 2-fold increase in the secretion of tumor necrosis factor (TNF). When added during differentiation, there was also a 25% decrease in lipid accumulation. In addition to the stimulation of TNF, TCDD affected glucose transport and lipoprotein lipase (LPL) activity. When added to cultures of cells that were undergoing differentiation, TCDD inhibited total 2-deoxyglucose transport in a dose-dependent fashion, with 50% inhibition of glucose transport when added to cultures for 48 hours at 5 nmol/L TCDD. In addition, when cells were exposed to 50 nmol/L TCDD for 48 hours, there was a 40% reduction in LPL activity. Thus, the addition of TCDD to adipocyte cultures resulted in an increase in TNF secretion and a decrease in glucose transport and LPL activity. Because TCDD is concentrated in adipose tissue, these studies provide a possible physiologic mechanism for epidemiologic studies that link dioxin to diabetes.
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PMID:The stimulation of tumor necrosis factor and inhibition of glucose transport and lipoprotein lipase in adipose cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1178 74

Lipolysis is an important process determining fuel metabolism, and insulin regulates this process in adipose tissue. The aim of this study was to investigate the long-term effects of insulin, an insulin enhancer (rosiglitazone [RSG]), and insulin in combination with RSG on the regulation of lipolysis and lipogenesis in human abdominal subcutaneous fat. Lipolysis and lipogenesis were assessed by protein expression studies of hormone-sensitive lipase (HSL) (84 kDa) and lipoprotein lipase (LPL) (56 kDa), respectively. In addition, lipolytic rate was assessed by glycerol release assay and tumor necrosis factor (TNF)-alpha release measured by enzyme-linked immunosorbent assay (n = 12). In subcutaneous adipocytes, increasing insulin doses stimulated LPL expression, with maximal stimulation at 100 nmol/l insulin (control, 1.0 +/- 0.0 [mean +/- SE, protein expression relative to control]; 1 nmol/l insulin, 0.87 +/- 0.13; 100 nmol/l insulin, 1.68 +/- 0.19; P < 0.001). In contrast, insulin at the 100 nmol/l dose reduced the expression of HSL (100 nmol/l insulin, 0.49 +/- 0.05; P < 0.05), while no significant reduction was observed at other doses. Higher doses of insulin stimulated both HSL (1,000 nmol/l insulin, 1.4 +/- 0.07; P < 0.01) and LPL (control 1.00 +/- 0.0; 1,000 nmol/l insulin, 2.66 +/- 0.27; P < 0.01) protein expression. Cotreatment with RSG induced an increased dose response to insulin for LPL and HSL (P < 0.05); RSG alone also increased LPL and HSL expression (P < 0.05). Insulin stimulated TNF-alpha secretion in a dose-dependent manner (P < 0.01); the addition of RSG (10(-8) mol/l) reduced TNF-alpha secretion (P < 0.05). In summary, chronic treatment of human adipocytes with insulin stimulates lipolysis and LPL protein expression. The addition of RSG reduced the lipolytic rate and TNF-alpha secretion. The increase in lipolysis is not explained by changes in HSL expression. These data, therefore, may explain in part why hyperinsulinemia coexists with increased circulating nonesterified free fatty acids and increased adiposity in obese and/or type 2 diabetic patients.
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PMID:Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro. 1197 47

We examined the role of intracellular Ca2+ in the mechanism of the preventive effects of the Ca2+-channel blocker verapamil against lipoprotein disturbances during tumor necrosis factor (TNFa)-induced shock syndrome. The heparin-releasable lipoprotein lipase (LPL) activity in plasma of TNFalpha (5 X 10(4) units/mouse, i.v.)-injected mice was markedly lower at 4 h post-intoxication than in the controls. In mice treated with verapamil (10 mg/kg, s.c.), the activity of LPL 4 h after TNFalpha injection was significantly higher than in mice treated with TNFalpha alone. On the other hand, on polyacrylamide gel disk electrophoresis, very low density lipoprotein (VLDL) and high density lipoprotein (HDL) fractions in the sera of TNFalpha-injected mice were increased and reduced, respectively, relative to the controls. The administration of verapamil clearly prevented the lipoprotein damage arising from TNFalpha challenge. We investigated whether verapamil could suppress TNFalpha generation in endotoxin-treated J774A.1 cells. Treatment with verapamil (30 microM) markedly inhibited endotoxin (1 microg/ml)-induced TNFalpha production in these cells. These findings suggest that the concentration of intracellular Ca2+ may contribute to the extent of lipoprotein disturbances in plasma, which results from LPL suppression in TNFalpha-induced shock syndrome. Verapamil may, therefore, protect against some of the various disturbances caused by changes in Ca2+ mobilization through its ability to inhibit TNFalpha production in septic shock.
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PMID:Preventive effects of a verapamil against tumor necrosis factor-alpha-induced shock symptoms: approached from lipoprotein metabolic disorders. 1218 28

Adipocytes have traditionally been considered to be the primary site for whole body energy storage mainly in the form of triglycerides and fatty acids. This occurs through the ability of insulin to markedly stimulate both glucose uptake and lipogenesis. Conventional wisdom held that defects in fuel partitioning into adipocytes either because of increased adipose tissue mass and/or increased lipolysis and circulating free fatty acids resulted in dyslipidemia, obesity, insulin resistance and perhaps diabetes. However, it has become increasingly apparent that loss of adipose tissue (lipodystrophies) in both animal models and humans also leads to metabolic disorders that result in severe states of insulin resistance and potential diabetes. These apparently opposite functions can be resolved by the establishment of adipocytes not only as a fuel storage depot but also as a critical endocrine organ that secretes a variety of signaling molecules into the circulation. Although the molecular function of these adipocyte-derived signals are poorly understood, they play a central role in the maintenance of energy homeostasis by regulating insulin secretion, insulin action, glucose and lipid metabolism, energy balance, host defense and reproduction. The diversity of these secretory factors include enzymes (lipoprotein lipase (LPL) and adipsin), growth factors [vascular endothelial growth factor (VEGF)], cytokines (tumor necrosis factor-alpha, interleukin 6) and several other hormones involved in fatty acid and glucose metabolism (leptin, Acrp30, resistin and acylation stimulation protein). Despite the large number of molecules secreted by adipocytes, our understanding of the pathways and mechanisms controlling intracellular trafficking and exocytosis in adipocytes is poorly understood. In this article, we will review the current knowledge of the trafficking and secretion processes that take place in adipocytes, focusing our attention on two of the best characterized adipokine molecules (leptin and adiponectin) and on one of the most intensively studied regulated membrane proteins, the GLUT4 glucose transporter.
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PMID:An adipocentric view of signaling and intracellular trafficking. 1239 77

The present study was undertaken to explore whether retinoids, which are known to have immunomodulatory actions, could attenuate tumor necrosis factor-alpha (TNF)-stimulated inducible nitric oxide synthase (iNOS) expression in 3T3-L1 adipocytes. Adipocytes incubated with TNF induced dose- and time-dependent accumulation of nitrite in the culture medium through the iNOS induction as confirmed by Western blotting. Treatment of cells with TNF in the presence of all-trans-retinoic acid (RA) significantly decreased their ability to produce nitrite and iNOS induction. Both 13-cis- and all- trans-RA-induced suppression was dose-dependent, and all-trans-RA was somewhat potent than 13-cis-RA. The inhibitory effect of RA on TNF-induced iNOS induction was reversible, completely recovered after 2 days, and was exerted through the inhibition of NF-kappaB activation. TNF also suppressed the lipoprotein lipase (LPL) activity of 3T3-L1 adipocytes. RA could not reverse the TNF- induced LPL suppression at RA levels causing near complete inhibition of the TNF-induced NO production. These results indicate that RAs attenuate iNOS expression reversibly in TNF-stimulated 3T3-L1 adipocytes, and that the TNF-induced LPL suppression is not the result of NO overproduction.
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PMID:Retinoic acid inhibits inducible nitric oxide synthase expression in 3T3-L1 adipocytes. 1252 99

Dramatic alternations in maternal metabolism occur during gestation and lactation, especially glucose and fat metabolism. For example, in rats, the amount of body fat mass increases during gestation, then decreases just prior to delivery, and remains low after parturition. To investigate the factors involved in such changes in maternal fat mass, messenger ribonucleic acid (mRNA) levels of adipocytokines, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and tumor necrosis factor-alpha (TNF-alpha), were examined in the intraabdominal adipose tissue of non-pregnant rats, pregnant rats and postpartum rats. We also examined the issue of whether apoptosis, which could be promoted by PPAR-gamma and TNF-alpha, is involved in any of the changes in maternal fat mass The activity of lipoprotein lipase (LPL) and hormone sensitive lipase (HSL) in adipose tissue was also measured. PPAR-gamma and TNF-alpha mRNA levels remained constant during the gestational and postpartum periods. Apoptosis was not detected at any time as evidenced by DNA laddering and in situ staining. LPL activity was significantly increased at day 5 and remained elevated until day 14 of gestation. HSL activity was significantly increased at day 10 of gestation and then decreased after delivery, at day 10 of lactation. In conclusion, during the gestational and postpartum period of rats, changes in maternal fat mass did not directly correlate with the levels of expression of PPAR-gamma and TNF-alpha mRNA. Apoptosis also does not appear to influence on fat mass change. The changes in LPL and HSL activities during gestation suggest that these enzymes might be regulators of maternal adipose tissue level.
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PMID:PPAR-gamma, TNF-alpha messenger RNA levels and lipase activity in the pregnant and lactating rat. 1255 54


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