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)

Primary culture of adipose tissue has often been used to investigate pharmacological and nutritional regulation of adipocyte gene expression. Possible alteration of adipocyte gene expression by primary culture on its own has not been explored in detail. In order to address this issue, explants were prepared from human subcutaneous adipose tissue recovered from plastic surgery and maintained for 0 to 48 h in DMEM supplemented with 10 % serum. At different time points, adipocytes were isolated from the explants by collagenase digestion, and mRNA expression and lipolysis were studied. Culture was associated with an accumulation of tumor necrosis factor-alpha (TNFalpha) in the culture medium, an increase in anaerobic glycolysis, and an increase in the basal lipolysis. In parallel, a rapid and dramatic decrease in the level of mRNA encoding for several adipocyte-specific proteins such as adipocyte lipid-binding protein, hormone-sensitive lipase, lipoprotein lipase, and peroxisome proliferation activating receptor-gamma2 was observed in isolated adipocytes. These downregulations were reminiscent of a dedifferentiation process. In parallel, primary culture was associated with an increase in adipocyte beta-actin, TNFalpha, glucose transporter-1 and hypoxia-induced factor-1alpha mRNAs. Treatment of explants with agents that increase cAMP (isobutylmethylxanthine and forskolin) prevented TNFalpha production and expression and culture-induced alterations of adipocyte gene expression. These data show that primary culture of human adipose tissue explants dramatically alters adipocyte gene expression.
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PMID:Culture of human adipose tissue explants leads to profound alteration of adipocyte gene expression. 1273 76

To elucidate the role of hormone-sensitive lipase (HSL) in diet-induced obesity, HSL-deficient (HSL-/-) and wild-type mice were fed normal chow or high-fat diets. HSL-/- mice were resistant to diet-induced obesity showing higher core body temperatures. Weight and triacylglycerol contents were decreased in white adipose tissue (WAT) but increased in both brown adipose tissue (BAT) and liver of HSL-/- mice. Serum insulin levels in the fed state and tumor necrosis factor-alpha mRNA levels in adipose tissues were higher, whereas serum levels of adipocyte complement-related protein of 30 kDa (ACRP30)/adiponectin and leptin, as well as mRNA levels of ACRP30/adiponectin, leptin, resistin, and adipsin in WAT, were lower in HSL-/- mice than in controls. Expression of transcription factors associated with adipogenesis (peroxisome proliferator-activated receptor-gamma, CAAT/enhancer-binding protein-alpha) and lipogenesis (carbohydrate response element-binding protein, adipocyte determination- and differentiation-dependent factor-1/sterol regulatory element-binding protein-1c), as well as of adipose differentiation markers (adipocyte lipid-binding protein, perilipin, lipoprotein lipase), lipogenic enzymes (glycerol-3-phosphate acyltransferase, acyl-CoA:diacylglycerol acyltransferase-1 and -2, fatty acid synthase, ATP citrate lyase) and insulin signaling proteins (insulin receptor, insulin receptor substrate-1, GLUT4), was suppressed in WAT but not in BAT of HSL-/- mice. In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL-/- mice. Our results suggest that impaired lipolysis in HSL deficiency affects lipid metabolism through alterations of adipose differentiation and adipose-derived hormone levels.
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PMID:Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice. 1295 98

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.
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PMID:Rapid downregulation of adipose tissue lipoprotein lipase activity on food deprivation: evidence that TNF-alpha is involved. 1469 8

The synthetic compound NO-1886 is a lipoprotein lipase activator that has been proven to be highly effective in lowering plasma triglycerides and elevating high-density lipoprotein cholesterol. Recently, we found that NO-1886 also had a plasma glucose-reducing action in high-fat/high-sucrose diet-induced diabetic rabbits. In the current study, we investigated the effects of NO-1886 on the morphology of adipocytes, plasma levels of tumor necrosis factor-alpha (TNF-alpha) and free fatty acids (FFA) in miniature pigs fed a high-fat/high-sucrose diet. Our results showed that feeding a high-fat/high-sucrose diet to miniature pigs increased the size of adipocytes, and the plasma levels of TNF-alpha, FFA, and glucose. This diet also induced insulin resistance and impaired the acute insulin response to glucose loading. Supplementing 1% NO-1886 to the high-fat/high-sucrose diet inhibited adipocyte enlargement, and suppressed plasma levels of TNF-alpha, FFA, and glucose. The decrease in plasma TNF-alpha and FFA was simultaneous with the decrease in plasma glucose. We also found an increased whole body glucose clearance and an increased acute insulin response to intravenous glucose loading by NO-1886 supplementation. These data suggest that NO-1886 improves the glucose metabolism in high-fat/high-sucrose diet-induced diabetic minipigs by decreasing fat deposit, and suppressing plasma TNF-alpha and FFA levels. Therefore, NO-1886 is potentially beneficial for the treatment of insulin-resistant syndrome.
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PMID:NO-1886 inhibits size of adipocytes, suppresses plasma levels of tumor necrosis factor-alpha and free fatty acids, improves glucose metabolism in high-fat/high-sucrose-fed miniature pigs. 1472 14

To elucidate the mechanism for hyperlipidemia in the hepatoma-bearing state, changes in some parameters related to the lipid metabolism and serum tumor necrosis factor-alpha (TNF-alpha) level were examined in Donryu rats that had been subcutaneously implanted with an ascites hepatoma cell line of AH109A. These parameters were also examined in rats that had been given a single injection of lipopolysaccharide (LPS), a model for acute infection with TNF-alpha secretion into the blood circulation. The serum triglyceride and total cholesterol (Ch) levels were significantly higher in both the hepatoma-implanted and LPS-injected rats than in normal rats. The level of adipose tissue lipoprotein lipase was decreased by hepatoma implantation and LPS injection, while the hormone-sensitive lipase activity was increased by the same treatments. Fatty acid (FA) oxidation and Ch synthesis were also stimulated by both treatments. The serum TNF-alpha level was noticably elevated by hepatoma implantation and greatly by the LPS injection. This LPS injection increased hepatic FA synthesis. The serum high-density lipoprotein Ch level and hepatic Ch 7alpha-hydroxylase activity were not changed by the LPS injection. Hepatoma implantation led to hyperlipidemia and elevated the serum TNF-alpha level, as did the LPS injection.
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PMID:Comparison of the changes in lipid metabolism between hepatoma-bearing and lipopolysaccharide-treated rats. 1474 66

This study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), tumor necrosis factor-alpha (TNF-alpha)); iii) thermogenesis and free fatty acid (FFA) transport/catabolism (uncoupling protein-1 (UCP1), lipoprotein lipase (LPL), beta2- and beta3-adrenergic receptor (beta2AR, beta3AR), fatty acid transport protein-1 (FATP-1) and iv) lipoproteins (apoliprotein E (apoE), apo CIII). The 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated. The single gene mutations such as C105 T OB and Pro115 Gln PPAR-gamma2 linked to morbid obesity were not detected in our group. A weak correlation between obesity and certain gene polymorphisms was observed. Being overweight (25 < BMI > or = 30 kg/m2) significantly correlated with worse FFA tolerance in male PPAR-gamma2 12Pro, LPL-H (G) allele carriers. Insulin resistance was found in female PPAR-gamma2 Pro12, TNF-alpha (-308A) and LPL-H (G) allele carriers. Hypertension linked to the PPAR-gamma2 Pro allele carriers was characterized by high leptin output during OLTT. We conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.
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PMID:Analysis of candidate genes in Polish families with obesity. 1520 83

hLpL(GPI) transgenic mice that overexpress human lipoprotein lipase (hLpL) with a glycosylphosphatidylinositol anchor on cardiomyocytes develop lipotoxic cardiomyopathy associated with increased cardiac uptake of plasma lipids. We hypothesized that peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, or a PPARalpha/gamma agonist would alter cardiac function by modulating lipid uptake by the heart. hLpL(GPI) mice were administered rosiglitazone (10 mg/kg/day), fenofibrate (100 mg/kg/day), or DRF2655, an alkoxy propanoic acid analog (10 mg/kg/day), for 16 days. Rosiglitazone reduced plasma triglyceride (TG) from 107.63 +/- 6.98 to 77.61 +/- 3.98 mg/dl, whereas fenofibrate had no effect. DRF2655 reduced TG to 33.17 +/- 4.12 mg/dl. Rosiglitazone and DRF2655 decreased heart TG and total cholesterol; fenofibrate had no effect. Molecular markers for cardiac dysfunction, atrial natriuretic factor, brain natriuretic peptide, and tumor necrosis factor-alpha were decreased with rosiglitazone and increased with fenofibrate. Echocardiographic measurements showed reduced fractional shortening and increased left ventricular systolic dimension with fenofibrate. No changes in these parameters were observed with rosiglitazone or DRF2655 treatment. Muscle-specific carnitine palmitoyltransferase-1 and fatty acid transporter protein-1 gene expression were increased with fenofibrate and DRF2655 treatment; no change in expression of these genes was noted with rosiglitazone treatment. Rosiglitazone and DRF2655 reduced TG uptake by the heart, and fenofibrate treatment increased fatty acid uptake. Thus, in a lipotoxic cardiomyopathy mouse model, a PPARgamma agonist reduced cardiac lipid and markers of cardiomyopathy, whereas an agonist of PPARalpha did not improve cardiac lipids and worsened heart function. These changes were paralleled by alterations in heart lipid uptake. Overall, PPAR activators exhibit differential effects in this model of lipotoxic dilated cardiomyopathy.
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PMID:Peroxisome proliferator-activated receptor agonists modulate heart function in transgenic mice with lipotoxic cardiomyopathy. 1567 Dec 4

Post-heparin plasma activity of lipoprotein lipase (LPL) and hepatic lipase (HL), and fat and muscle activity of LPL were measured in neutered lean and obese cats. Lipoprotein lipase, hormone-sensitive lipase (HSL), and tumor necrosis factor a (TNF) mRNA were measured in muscle and fat tissue with real-time PCR using primers for feline LPL, HSL, and TNF. Lipoprotein lipase plasma and fat activity and fat mRNA levels were significantly lower (50, 80, and 50%, respectively) in obese cats than lean cats, whereas the muscle/fat ratio of LPL was significantly higher in obese compared to lean cats. The activity of HL was not different between the groups. Hormone-sensitive lipase mRNA levels were significantly higher in obese than lean cats. The level of fat TNF also was significantly higher in obese cats than in lean cats, whereas the level in muscle was not different. The lower LPL activity and mRNA expression in fat and the higher LPL and HSL mRNA expression in muscle in obese cats compared to lean cats expectedly favor a redistribution of fatty acids from fat to muscle tissue where they can be deposited or used for energy in times of need. Tumor necrosis factor alpha may regulate this repartitioning process through suppression of adipocyte LPL.
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PMID:Activity and tissue-specific expression of lipases and tumor-necrosis factor alpha in lean and obese cats. 1621 42

Fenofibrate, a selective (1)PPAR-alpha activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-alpha reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-alpha activators may be useful in the treatment of syndrome X.
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PMID:Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. 1647 80

Dietary model of steatohepatitis was established by feeding mice a methionine choline deficient (MCD) diet. Mice on MCD or control diet for 3 weeks were treated with or without NO-1886, a newly synthetic lipoprotein lipase (LPL) activator. In a separate experiment, NO-1886 was given after pre-treatment with 3 weeks of MCD diet. NO-1886 significantly reduced MCD-induced inflammation by repressing levels of hepatic lipid peroxides and pro-inflammatory tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). In addition, NO-1886 dampened hepatic steatosis via accelerating fatty acid oxidation caused by enhanced expression of PPARalpha, cytochrome P450-10 (Cyp4a10), and Acyl-CoA oxidase (ACO). It failed to regulate genes of fatty acid uptake and synthesis pathways. In conclusion, NO-1886 ameliorated and induced regression of experimental steatohepatitis via increasing endogenous LPL activation resulting in suppression on pro-inflammatory factors and reduction of hepatic fatty acids. These findings indicate that NO-1886 is a potential therapeutic agent for steatohepatitis.
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PMID:Lipoprotein lipase activator ameliorates the severity of dietary steatohepatitis. 1735 May 93


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