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)

The hypolipidemic fibrates and antidiabetic thiazolidinediones display potent triglyceride-lowering activities. Studies on the molecular action mechanisms of these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased expression of lipoprotein lipase (LPL) and decreased expression of apolipoprotein (apo) C-III, both key-players in plasma triglyceride metabolism. Fibrates, on the one hand, are PPAR alpha activators, which selectively induce LPL mRNA levels and activity in the liver. Furthermore, hepatic apo C-III mRNA levels and protein production strongly decrease after fibrate treatment. On the other hand, thiazolidinediones, which are high affinity ligands for PPAR gamma, have no effect in the liver, but act primarily on adipose tissue, where they induce LPL mRNA levels and activity. The modulation of the expression of the LPL and apo C-III genes in liver and adipose tissue is correlated with the tissue-specific distribution of the respective PPARs (PPAR gamma expression being restricted to adipose tissue, whereas PPAR alpha is expressed predominantly in liver) confirming that fibrates and thiazolidinediones exert their effects primarily through PPAR alpha and PPAR gamma respectively. This distinct tissue-specific transcriptional regulation of genes involved in lipid metabolism by fibrates and thiazolidinediones indicates that research of compounds displaying combined PPAR alpha and PPAR gamma activation potential should lead to the discovery of more potent triglyceride-lowering drugs, which may be of use in the treatment of hypertriglyceridemia.
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PMID:The effects of fibrates and thiazolidinediones on plasma triglyceride metabolism are mediated by distinct peroxisome proliferator activated receptors (PPARs). 920 2

The molecular mechanism by which hypolipidemic fibrates and antidiabetic thiazolidinediones exert their hypotriglyceridemic action are discussed. Increased activity of lipoprotein lipase (LPL), a key lipolytic enzyme, and decreased levels of apolipoprotein C-III (apo C-III) seem to explain the hypotriglyceridemic effects of compounds. Both fibrates and thiazolidinediones exert their action by activating transcription factors of the peroxisome proliferator activated receptor (PPAR) family, thereby modulating the expression of the LPL and apo C-II genes. First, treatment of rats with PPAR alpha activators, such as fibrates induced LPL mRNA and activity selectively in the liver. In contrast, the thiazolidinediones, which are high affinity ligands for PPAR gamma, have no effect on liver, but induce LPL mRNA and activity levels in adipose tissue. In hepatocytes, fibrates, unlike the thiazolidinediones, induce LPL mRNA levels, whereas in preadipocyte cell lines the PPAR gamma ligand induces LPL mRNA levels much quicker and to a higher extent than fibrates. Second, apo C-III mRNA and protein production strongly decrease in livers of fibrate but not thiazolidinedione-treated animals. Fibrates also reduced apo C-III production in primary cultures of rat and human hepatocytes. The modulation of the expression of the LPL and apo C-III genes by either PPAR alpha or gamma activators, correlates with the tissue-specific distribution of the respective PPARs: PPAR gamma expression is restricted to adipose tissues, whereas PPAR alpha is expressed predominantly in liver. In both the LPL and apo C-III genes, sequence elements responsible for the modulation of their expression by activated PPARs have been identified which supports that the transcriptional regulation of these genes by fibrates and thiazolidinediones contributes significantly to their hypotriglyceridemic effects in vivo. Whereas thiazolidinediones predominantly affect adipocyte LPL production through activation of PPAR gamma, fibrates exert their effects mainly in the liver via a PPAR alpha-mediated reduction in apo C-III production. This tissue specific transcriptional regulation of genes involved in lipid metabolism by PPAR activators and/or ligands might have important therapeutic implications.
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PMID:Regulation of triglyceride metabolism by PPARs: fibrates and thiazolidinediones have distinct effects. 922 59

Transcription factor transcripts implicated in adipocyte differentiation (peroxisome proliferator-activated receptor gamma (PPAR gamma), retinoid x receptor alpha (RXR alpha), adipocyte determination and differentiation-dependent factor 1 (ADD1), and CCAAT/enhancer binding protein alpha (C/EBP alpha)) and adipocyte-characteristic protein transcripts (lipoprotein lipase (LPL) and adipocyte fatty acid binding protein (aP2)) were measured in pig tissues. Transcripts for PPAR gamma, ADD1, and aP2 were localized in porcine subcutaneous and perirenal adipose tissues; transcripts for C/EBP alpha and LPL were detected in other tissues, but the greatest concentrations were in the adipose tissues. In porcine stromal-vascular cells (S/V cells) differentiating in vitro, transcripts for PPAR gamma and aP2 increased gradually, transcripts for ADD1, and LPL increased early and transcripts for C/EBP alpha increased late. In pigs, adipose tissue transcripts for PPAR gamma, ADD1, and LPL were minimal at birth and increased to 28 days postpartum, transcripts for C/EBP alpha were low until 28 days and transcripts for aP2 were at high levels, regardless of age. Although transcript development was somewhat different in vitro and in vivo, the data suggest PPAR gamma (and ADD1 are involved in regulation of transcripts for LPL and that there may be more partially differentiated precursor cells in S/V cells at day 0 than in adipose tissue at birth.
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PMID:Expression of porcine adipocyte transcripts: tissue distribution and differentiation in vitro and in vivo. 1048 Dec 59

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. PPAR activators have effects on both metabolic risk factors and on vascular inflammation related to atherosclerosis. PPAR have profound effects on the metabolism of lipoproteins and fatty acids. PPAR alpha binds hypolipidemic fibrates, whereas PPAR gamma has a high affinity for antidiabetic glitazones. Both PPAR are activated by fatty acids and their derivatives. Activation of PPAR alpha increases the catabolism of fatty acids at several levels. In the liver, it increases uptake of fatty acids and activates their beta-oxidation. The effects that PPAR alpha exerts on triglyceride-rich lipoproteins is due to their stimulation of lipoprotein lipase and repression of apolipoprotein CIII expression, while the effects on high-density lipoproteins depend upon the regulation of apolipoproteins AI and AII. PPAR gamma has profound effects on the differentiation and function of adipose tissue, where it is highly expressed. PPAR are also expressed in atherosclerotic lesions. PPAR are present in vascular endothelial cells, smooth muscle cells, monocytes, and monocyte-derived macrophages. Via negative regulation of nuclear factor-kappa B and activator protein-1 signalling pathways, PPAR alpha inhibits expression of inflammatory genes, such as interleukin-6, cyclooxygenase-2, and endothelin-1. Furthermore, PPAR alpha inhibits expression of monocyte-recruiting proteins such as vascular cell adhesion molecule (VCAM)-1 and induces apoptosis in monocyte-derived macrophages. PPAR gamma activation in macrophages and foam cells inhibits the expression of activated genes such as inducible nitric oxide synthase, matrix metalloproteinase-9 and scavenger receptor A. PPAR gamma may also affect the recruitment of monocytes in atherosclerotic lesions as it is involved in the expression of VCAM-1 and intracellular adhesion molecule-1 in vascular endothelial cells. The involvement of PPAR in atherosclerosis, a disease with a chronic inflammatory character, suggests that they may play a role in other inflammatory-related diseases as well.
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PMID:Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. 1100 63

This study was performed to compare the expression of key proteins [lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), complement 3 (C3), and peroxisome proliferator-stimulated receptor-gamma (PPAR gamma)] involved in sc abdominal adipose tissue (AT) metabolism of young (n = 13) vs. middle-aged (n = 16) men. The sc abdominal AT-LPL activity as well as fat cell lipolysis were also measured in both groups of men. Young and middle-aged men displayed similar body weight and sc abdominal fat accumulation, measured by computed tomography. However, middle-aged men were characterized by a higher percent body fat (28 +/- 5% vs. 22 +/- 7%; P < 0.05) than young subjects. No difference between groups was observed in sc abdominal adipose tissue LPL activity. On the other hand, maximal lipolytic responses of sc abdominal adipocytes to isoproterenol (beta-adrenergic agonist) or to postadrenoceptor agents such as dibutyryl cAMP, forskolin, and theophylline were lower in middle-aged than in young men (P < 0.05). AT-LPL messenger ribonucleic acid (mRNA) levels were similar regardless of the subject's age. However, HSL, C3, and PPAR gamma mRNA levels were higher in middle-aged than in young individuals (P < 0.01-0.05). After correction for percent body fat, only HSL and C3 mRNA levels remained significantly different between groups (P < 0.05). Taken together, these results suggest that aging has an effect on the up-regulation of HSL and C3 mRNA levels, whereas PPAR gamma expression seems to be related mainly to increased adiposity.
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PMID:Age-related differences in messenger ribonucleic acid expression of key proteins involved in adipose cell differentiation and metabolism. 1115 53

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.
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PMID:Expression of insulin target genes in skeletal muscle and adipose tissue in adult patients with growth hormone deficiency: effect of one year recombinant human growth hormone therapy. 1169 48

Disruption of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene causes embryonic lethality due to placental dysfunction. To circumvent this, a PPAR gamma conditional gene knockout mouse was produced by using the Cre-loxP system. The targeted allele, containing loxP sites flanking exon 2 of the PPAR gamma gene, was crossed into a transgenic mouse line expressing Cre recombinase under the control of the alpha/beta interferon-inducible (MX) promoter. Induction of the MX promoter by pIpC resulted in nearly complete deletion of the targeted exon, a corresponding loss of full-length PPAR gamma mRNA transcript and protein, and marked reductions in basal and troglitazone-stimulated expression of the genes encoding lipoprotein lipase, CD36, LXR alpha, and ABCG1 in thioglycolate-elicited peritoneal macrophages. Reductions in the basal levels of apolipoprotein E (apoE) mRNA in macrophages and apoE protein in total plasma and high-density lipoprotein (HDL) were also observed in pIpC-treated PPAR gamma-MXCre(+) mice. Basal cholesterol efflux from cholesterol-loaded macrophages to HDL was significantly reduced after disruption of the PPAR gamma gene. Troglitazone selectively inhibited ABCA1 expression (while rosiglitazone, ciglitazone, and pioglitazone had little effect) and cholesterol efflux in both PPAR gamma-deficient and control macrophages, indicating that this drug can exert paradoxical effects on cholesterol homeostasis that are independent of PPAR gamma. Together, these data indicate that PPAR gamma plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.
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PMID:Conditional disruption of the peroxisome proliferator-activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. 1190 55

The thiazolidinediones (TZDs) or 'glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma), a nuclear receptor. TZD-induced activation of PPAR gamma alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and the GLUT4 glucose transporter. TZDs reduce insulin resistance in adipose tissue, muscle and the liver. However, PPAR gamma is predominantly expressed in adipose tissue. It is possible that the effect of TZDs on insulin resistance in muscle and liver is promoted via endocrine signalling from adipocytes. Potential signalling factors include free fatty acids (FFA) (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumour necrosis factor-alpha (TNF-alpha), which is overexpressed in obesity and insulin resistance. Although there are still many unknowns about the mechanism of action of TZDs in type 2 diabetes, it is clear that these agents have the potential to benefit the full 'insulin resistance syndrome' associated with the disease. Therefore, TZDs may also have potential benefits on the secondary complications of type 2 diabetes, such as cardiovascular disease.
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PMID:The mode of action of thiazolidinediones. 1192 33

The two major metabolic perturbations resulting in hyperglycaemia in type 2 diabetes are insulin resistance and insulin deficiency. Insulin resistance occurs in peripheral organs (muscle and fat), leading to decreased glucose uptake and utilisation, and in liver, leading to increased hepatic glucose production. Thiazolidinediones, pharmacological ligands for PPAR gamma, can modulate the expression of genes influencing carbohydrate and lipid metabolism. Pioglitazone, a recently introduced thiazolidinedione, improves glycaemic control and lipid profiles in people with type 2 diabetes. Some of the possible mechanisms of improving glycaemic control include (a) increase in GLUT-1 and GLUT-4, (b) enhancement of insulin signalling, (c) decrease in tumour necrosis factor-alpha action, (d) reduction in plasma free fatty acid and (e) decrease in PEPCK. Together these can increase glucose uptake and utilisation in the peripheral organs and decrease gluconeogenesis in the liver. Possible mechanisms resulting in more desirable lipid profiles include an increase in phosphodiesterase-3B resulting in reduced intra-cellular lipolysis in adipocytes and an increase in lipoprotein lipase resulting in enhanced clearance of triglyceride-rich lipoproteins(TRLs). Pioglitazone, used as monotherapy or in combination with sulphonylurea, biguanide or insulin, improves glycaemic control, lowers serum triglycerides and raises high density lipoprotein (HDL)-cholesterol. It enhances hepatic and peripheral insulin sensitivity. In clinical trials, there has been no evidence of hepatotoxicity or increased incidence of elevated serum ALT in subjects taking pioglitazone compared with placebo.
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PMID:Current treatment of insulin resistance in type 2 diabetes mellitus. 1196 33

The trans-10,cis-12 isomer of conjugated linoleic acid (CLA) has been shown to reduce body fat gain in mice. However, the underlying molecular mechanism is not well characterized. Here we report evidence that trans-10,cis-12 (t10c12) CLA inhibits preadipocyte differentiation. Treating differentiating 3T3-L1 preadipocytes with t10c12 CLA and conjugated nonadecadienoic acid (CNA, a 19-carbon CLA cognate) resulted in decreased intracellular triglyceride accumulation and mRNA levels of the adipogenic gene fatty acid synthase and adipocyte lipid binding protein. T10c12 CLA and CNA also reduced protein levels of adipocyte transcription factors, peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding protein alpha. Similarly, CLA reduced body fat gain and significantly inhibited the expression of PPAR gamma and its downstream target lipoprotein lipase in mouse adipose tissue. These observations indicate that CLA decreases body fat gain in part by inhibiting the differentiation of preadipocytes.
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PMID:trans-10,cis-12 CLA inhibits differentiation of 3T3-L1 adipocytes and decreases PPAR gamma expression. 1267 Apr 81


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