Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.34 (lipoprotein lipase)
 7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central role of the intracellular enzyme hormone-sensitive lipase (HSL) in regulating fatty acid metabolism makes it an interesting pharmacological target for the treatment of insulin resistant and dyslipidemic disorders where a decrease in delivery of fatty acids to the circulation is desirable, e.g., in individuals with type 2 diabetes, metabolic syndrome, or impaired glucose tolerance. On the basis of a lead structure from high throughput screening, we have identified a very potent type of carbamoyl-triazole inhibitors of HSL. As part of the lead optimization program, four new classes of carbamoyl-triazoles were synthesized and tested with respect to potency, efficacy and selectivity. Methyl-phenyl-carbamoyl-triazoles were identified as potent and efficacious HSL inhibitors. These compounds do not inhibit other hydrolases such as hepatic lipase, lipoprotein lipase, pancreatic lipase, and butyrylcholine esterase. However, the inhibitors 4b and 4g with IC(50) values for HSL of 0.17 and 0.25 microM, respectively, were the only inhibitors selective against acetylcholine esterase. A reversible pseudosubstrate inhibition mechanism is proposed for this class of inhibitors.
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PMID:Synthesis and structure-activity relationship for a novel class of potent and selective carbamoyl-triazole based inhibitors of hormone sensitive lipase. 1471 11

Endothelial lipase (LIPG) is the latest addition to the triglyceride lipase family of genes that includes pancreatic lipase (PL), hepatic lipase (HL), and lipoprotein lipase (LPL). These lipolytic enzymes demonstrate both triglyceride lipase as well as phospholipase activities and are integrally involved in lipid absorption, transport, and metabolism. Several studies have demonstrated that LIPG is important for affecting lipid levels in mice but the data in humans is less complete. To more thoroughly characterize the LIPG gene, we resequenced it from an ethnically diverse population. Thirteen novel single-nucleotide polymorphisms (SNPs) were identified and seven others confirmed. High linkage disequilibrium was found among these SNPs spanning the length of the transcript, allowing interrogation of the entire gene for functional variation. Subjects with either high or low HDL cholesterol were used to investigate its association with LIPG gene variation. Associations were found with the most significant being the intronic variants C+42T/In5 and T+2864C/In8 (P=0.007 and 0.004, respectively). A trend for an association of the same SNPs with fewer myocardial infarctions (P=0.03) was also observed but was not significant after correction for multiple testing. The results of this study provide data linking variation in the human LIPG gene with HDL cholesterol levels as well as further evidence in support of LIPG as a potential target for therapeutic intervention.
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PMID:Association between single-nucleotide polymorphisms in the endothelial lipase (LIPG) gene and high-density lipoprotein cholesterol levels. 1498 37

The aim of this study was to investigate the specificity of the 3H-triolein assay and to investigate the recovery of highly purified pancreatic lipase and pancreatic lipase in the form of pure non-activated pig pancreatic juice. Blood plasma from pigs was analysed for pancreatic lipase activity using the 3H-triolein substrate assay, with a method specific for lipoprotein lipase and with a method specific for hepatic lipase. The recovery of pancreatic lipase from pancreatic juice was approximately 100%, while the recovery of highly purified pancreatic lipase in plasma or whole blood was found to be approximately 1%. Preparations of highly concentrated, purified lipoprotein lipase showed activity in the 3H-triolein assay designed for pancreatic lipase, but the activity did not exceed 1% of the activity of this enzyme measured in an assay specific for lipoprotein lipase (samples containing physiological levels of lipoprotein lipase did not show any activity in the assay). Hepatic lipase was not measurable under the conditions of the 3H-triolein assay. In conclusion, the 3H-triolein assay showed pronounced specificity for pancreatic lipase compared with lipoprotein lipase or hepatic lipase.
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PMID:Specificity of the 3H-triolein assay for pancreatic lipase in blood plasma. 1623 87

The aim of the present study was to assess the effects of peanut (Arachis hypogaea L.) shell extracts (PSE) on lipases and to evaluate its potential development for the treatment of obesity. The peanut shells were extracted in 95% ethanol, and the extracts were screened for inhibitory effects on pancreatic lipase (PL) and lipoprotein lipase (LPL) activities as well as on lipolysis of 3T3-L1 adipocytes. We also examined in vivo whether PSE could prevent the body weight gain induced by feeding a high-fat diet to male Wistar rats for 12 weeks. PSE inhibits a number of lipases, including PL, LPL and, possibly, hormone sensitive lipase (HSL). PSE-treated Wistar rats showed increased fecal lipid excretion respect to the control group. Body weight and body weight gain, and liver size, were significantly lower in rats fed the high-fat diet with 1% of PSE (w:w diet) than in those fed the high-fat diet alone. The rats treated with PSE showed reduced triacylglycerol content in the liver, as well as the serum glucose and insulin. The inhibitory activity of PSE on the lipid metabolic enzymes and the increase in fecal fat excretion suggests that PSE might be useful as a treatment to reduce the dietary fat absorption. The observed reduction in intracellular lipolytic activity of cultured 3T3-L1 adipocytes may reduce the levels of circulating free fatty acids. The observed effects are likely induced by more than one bioactive component of PSE. The PSE actions may, at least in part, be attributed to the inhibition of fat absorption in the digestive tract and the reduction of the adipocyte lipolysis.
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PMID:Effects of Arachis hypogaea nutshell extract on lipid metabolic enzymes and obesity parameters. 1633 40

Lipases sensitive to organophosphorus (OP) inhibitors play critical roles in cell regulation, nutrition, and disease, but little is known on the toxicological aspects in mammals. To help fill this gap, six lipases or lipase-like proteins are assayed for OP sensitivity in vitro under standard conditions (25 degrees C, 15 min incubation). Postheparin serum lipase, lipoprotein lipase (LPL) (two sources), pancreatic lipase, monoacylglycerol (MAG) lipase, cholesterol esterase, and KIAA1363 are considered with 32 OP pesticides and related compounds. Postheparin lipolytic activity in rat serum is inhibited by 14 OPs, including chlorpyrifos oxon (IC50 50-97 nM). LPL (bovine milk and Pseudomonas) generally is less inhibited by the insecticides or activated oxons, but the milk enzyme is very sensitive to six fluorophosphonates and benzodioxaphosphorin oxides (IC50 7-20 nM). Porcine pancreatic lipase is very sensitive to dioctyl 4-nitrophenyl phosphate (IC50 8 nM), MAG lipase of mouse brain to O-4-nitrophenyl methyldodecylphosphinate (IC50 0.6 nM), and cholesterol esterase (bovine pancreas) to all of the classes of OPs tested (IC50 < 10 nM for 17 compounds). KIAA1363 is sensitive to numerous OPs, including two O-4-nitrophenyl compounds (IC50 3-4 nM). In an overview, inhibition of 28 serine hydrolases (including lipases) by eight OPs (chlorpyrifos oxon, diazoxon, paraoxon, dichlorvos, and four nonpesticides) showed that brain acetylcholinesterase is usually less sensitive than butyrylcholinesterase, liver esterase, cholesterol esterase, and KIAA1363. In general, each lipase (like each serine hydrolase) has a different spectrum of OP sensitivity, and individual OPs have unique ranking of potency for inhibition of serine hydrolases.
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PMID:Each lipase has a unique sensitivity profile for organophosphorus inhibitors. 1644 51

To investigate the nutritional regulation of lipid metabolism in fish, molecular characterization of lipases was conducted in red sea bream Pagrus major, and the effects of fasting and refeeding on their gene expression was examined. Together with data from a previous study, a total of four lipase genes were identified and characterized as lipoprotein lipase (LPL), hepatic lipase (HL) and pancreatic lipase (PL). These four lipase genes, termed LPL1, LPL2, HL and PL, share a high degree of similarity. LPL1 and LPL2 genes were expressed in various tissues including adipose tissue, gill, heart and hepatopancreas. HL gene was exclusively expressed in hepatopancreas. PL gene expression was detected in hepatopancreas and adipose tissue. Red sea bream LPL1 and LPL2 gene expression levels in hepatopancreas were increased during 48 h of fasting and decreased after refeeding, whereas no significant change in the expression levels of LPL1 and LPL2 was observed in adipose tissue, indicating that LPL1 and LPL2 gene expression is regulated in a tissue-specific manner in response to the nutritional state of fish. HL and PL gene expression was not affected by fasting and refeeding. The results of this study suggested that LPL, HL and PL gene expression is under different regulatory mechanisms in red sea bream with respect to the tissue-specificities and their nutritional regulation.
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PMID:Molecular characterization of lipoprotein lipase, hepatic lipase and pancreatic lipase genes: effects of fasting and refeeding on their gene expression in red sea bream Pagrus major. 1690 58

Although inhibitors of the enzymatic hydrolysis of the endocannabinoid 2-arachidonoylglycerol are available, they are either rather weak in vitro (IC(50)>30 microM) or their selectivity towards other proteins of the endocannabinoid system has not been tested. Here we describe the synthesis and activity in vitro and in vivo of a tetrahydrolipstatin analogue, OMDM169, as a potent inhibitor of 2-AG hydrolysis, capable of enhancing 2-AG levels and of exerting analgesic activity via indirect activation of cannabinoid receptors. OMDM169 exhibited 0.13 microM<IC(50)<0.41 microM towards 2-AG hydrolysing activities in COS-7 cells and rat cerebellum, and inhibited (IC(50)=0.89 microM) the human recombinant MAGL, whilst being inactive (K(i)>10 microM) at human CB(1) and CB(2) receptors. However, OMDM169 shared with tetrahydrolipstatin the capability of inhibiting the human pancreatic lipase (IC(50)=0.6 microM). OMDM169 inhibited fatty acid amide hydrolase and diacylglycerol lipase only at higher concentrations (IC(50)=3.0 and 2.8 microM, respectively), and, accordingly, it increased by approximately 1.6-fold the levels of 2-AG, but not anandamide, in intact ionomycin-stimulated N18TG2 neuroblastoma cells. Acute intraperitoneal (i.p.) administration of OMDM169 to mice inhibited the second phase of the formalin-induced nocifensive response with an IC(50) of approximately 2.5 mg/kg, and concomitantly elevated 2-AG, but not anandamide, levels in the ipsilateral paw of formalin-treated mice. The antinociceptive effect of OMDM169 was antagonized by antagonists of CB(1) and CB(2) receptors, AM251 and AM630, respectively (1 mg/kg, i.p.). OMDM69 might represent a template for the development of selective and even more potent inhibitors of 2-AG hydrolysis.
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PMID:Development of a potent inhibitor of 2-arachidonoylglycerol hydrolysis with antinociceptive activity in vivo. 1902 77

Emerging evidence suggests that consumption or supplementation of foods rich in iso flavones may has a beneficial effect on obesity and glucose levels in animals and humans. It has been demonstrated that genistein, the main component of iso fl avones, could significantly reduce body weight and fat pad size. However, there is no evidence as to whether daidzein, which is also a main component of isoflavones, has the same effect. We hypothesize that LRXH609 (Dzd; a daidzein derivative) also has an antiobesity effect. In this study, we investigate the effects of Dzd on body weight, adipose tissue, blood, and liver lipid levels in obese mice fed a high-fat diet. Activities of pancreatic lipase and lipoprotein lipase, as well as lipolysis, were verified to clarify the potential mechanism of the daidzein. The results indicate that Dzd can significantly reduce body and fat pad weight and ameliorate the high-fat diet-induced hyperlipoidemia. We also found that Dzd inhibits the activity of pancreatic lipase and lipoprotein lipase in a dose-dependent manner, inhibits the differentiation of rat preadipocytes, and stimulates lipolysis by activating hormone-sensitive lipase.
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PMID:Antiobesity action of a daidzein derivative on male obese mice induced by a high-fat diet. 1985 81

Pleurotus eryngii water extract (PEE), which showed the most significant inhibitory activity against pancreatic lipase in vitro among eight edible mushrooms, was investigated to determine the mechanism of its anti-lipase activity in vitro and its hypolipidemic effect in fat-loaded mice. The inhibitory effects of mushroom extracts on pancreatic lipase activity were examined using 4-methylumbelliferyl oleate (4-MUO) or trioleoylglycerol emulsified with lecithin, gum arabic or Triton X-100 as a substrate. For in vivo experiments, blood samples were taken after oral administration of corn oil and [(3)H]trioleoylglycerol with or without PEE to food-deprived mice. PEE inhibited hydrolysis of 4-MUO and trioleoylglycerol emulsified with lecithin or Triton X-100, but not that of trioleoylglycerol emulsified with gum arabic. PEE suppressed the elevations of plasma and chylomicron triacylglycerol levels after oral administration of corn oil, but had no effect on lipoprotein lipase activity. [(3)H]Trioleoylglycerol absorption was also decreased by administration of PEE. The results of in vitro studies suggest that PEE may prevent interactions between lipid emulsions and pancreatic lipase. The hypolipidemic effect of PEE in fat-loaded mice may be due to low absorption of fat caused by the inhibition of pancreatic lipase.
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PMID:Hypolipidemic effect of Pleurotus eryngii extract in fat-loaded mice. 2035 46

Endothelial lipase (gene: LIPG; enzyme: EL) is one of three members of the triglyceride lipase family that contributes to lipoprotein degradation within the circulation system and plays a major role in HDL metabolism in the body. In this study, in silico methods were used to predict the amino acid sequences, secondary and tertiary structures, and gene locations for LIPG genes and encoded proteins using data from several vertebrate genome projects. LIPG is located on human chromosome 18 and is distinct from other human 'neutral lipase' genes, hepatic lipase (gene: LIPC; enzyme: HL) and lipoprotein lipase (gene: LPL; enzyme: LPL) examined. Vertebrate LIPG genes usually contained 10 coding exons located on the positive strand for most primates, as well as for horse, bovine, opossum, platypus and frog genomes. The rat LIPG gene however contained only 9 coding exons apparently due to the presence of a 'stop' codon' within exon 9. Vertebrate EL protein subunits shared 58-97% sequence identity as compared with 38-45% sequence identities with human HL and LPL. Four previously reported human EL N-glycosylation sites were predominantly conserved among the 10 potential N-glycosylation sites observed for the vertebrate EL sequences examined. Sequence alignments and identities for key EL amino acid residues were observed as well as conservation of predicted secondary and tertiary structures with those previously reported for horse pancreatic lipase (PL) (Bourne et al. 1994). Several potential sites for regulating LIPG gene expression were observed including CpG islands near the LIPG gene promoter and a predicted microRNA binding site near the 3'-untranslated region. Promoter regions containing functional polymorphisms that regulate HDL cholesterol in baboons were conserved among primates but not retained between primates and rodents. Phylogenetic analyses examined the relationships and potential evolutionary origins of the vertebrate LIPG gene subfamily with other neutral triglyceride lipase gene families, LIPC and LPL. It is apparent that the triglyceride lipase ancestral gene for the vertebrate LIPG gene predated the appearance of fish during vertebrate evolution >500 million years ago.
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PMID:Vertebrate endothelial lipase: comparative studies of an ancient gene and protein in vertebrate evolution. 2126 36


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