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)

Chronic renal failure (CRF) is associated with hypertriglyceridemia and elevated plasma VLDL and IDL concentrations. These events can be due to either increased production or depressed catabolism of triglyceride-rich lipoproteins. Several studies have documented downregulation of lipoprotein lipase, hepatic triglyceride lipase, and the VLDL receptor, leading to depressed clearance and elevated plasma concentration of triglyceride-rich lipoproteins and their remnants in CRF. However, the effect of CRF on the triglyceride biosynthetic pathway has not been explored. Diglycerol acyltransferase (DGAT) is a microsomal enzyme that joins acyl-CoA to 1,2 diacylglycerol and, as such, constitutes the final step in triglyceride biosynthesis. Two distinct forms of DGAT (DGAT-1 and -2) have thus far been identified. The present study was undertaken to examine the effect of CRF on DGAT gene expression and activity in the liver, which is the source of endogenous triglycerides in the circulation. Male Sprague-Dawley rats were studied 8 wk after 5/6 nephrectomy (CRF) or sham operation. DGAT-1 and DGAT-2 mRNA abundance and DGAT activity were quantified. The CRF group showed reduced creatinine clearance, elevated plasma triglycerides, and VLDL concentrations. This was accompanied by significant reductions in hepatic DGAT-2 mRNA abundance (P < 0.01) and total DGAT activity (P < 0.1), pointing to diminished hepatic triglyceride production capacity in CRF animals. In conclusion, CRF results in significant downregulation of hepatic DGAT gene expression and activity. Given the critical role of DGAT in triglyceride biosynthesis, the present study points to diminished, not increased, hepatic triglyceride synthetic capacity in CRF rats.
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PMID:Downregulation of hepatic acyl-CoA:diglycerol acyltransferase in chronic renal failure. 1501 Mar 58

Chronic renal failure (CRF) frequently results in hypertriglyceridemia and elevated plasma concentration of very-low-density lipoprotein (VLDL). These abnormalities are thought to be primarily due to depressed lipoprotein lipase and hepatic lipase activities, as well as impaired clearance of plasma lipoproteins. Some results suggest that not only lipoproteins catabolism but also their overproduction might contribute to hypertriglyceridemia in CRF. Because sterol regulatory element binding protein (SREBP) plays an important role in the regulation of lipid homeostasis, increased level of this transcription factor might be involved in modulating lipid metabolism in CRF. The purpose of the present study is to determine whether there is an altered regulation of the SREBP-1 in CRF rats and whether the altered regulation of SREBP-1 is associated with the upregulation of lipogenic enzymes genes expression in CRF rats. In the white adipose tissue (WAT) of CRF rats, marked increases in the microsomal (precursor) and nuclear (mature) forms of SREBP-1 have been found. The increase in SREBP-1 was associated with an increased level of lipogenic enzymes (acetyl-coenzyme A [CoA] carboxylase [ACC], adenosine triphosphate-citrate lyase [ACL], fatty acid synthase [FAS], glucose 6-phosphate dehydrogenase [G6PDH], 6-phosphogluconate dehydrogenase [6PGDH], and malic enzyme [ME]) genes expression. In turn, this was associated with an increased rate of fatty acids synthesis in WAT and a significant increase in plasma triacylglycerol (TAG) and VLDL concentration. Our study indicates that WAT SREBP-1 expression is increased in CRF rats and that SREBP-1 may play an important role in the increased fatty acid synthesis. These results reveal another facet of disturbed lipid metabolism in CRF.
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PMID:Upregulation of lipogenic enzymes genes expression in white adipose tissue of rats with chronic renal failure is associated with higher level of sterol regulatory element binding protein-1. 1528 Oct 19

Aging is a process that affects different organs, of which the brain is particularly susceptible. PA and DAG are central intermediates in the phosphoglyceride as well as in the neutral lipid biosynthetic pathway, and they have also been implicated in signal transduction. Phospholipase D (PLD) and phosphatidate phosphohydrolase (PAP) are the enzymes that generate PA and DAG. The latter can be transformed into MAG by diacylglycerol lipase (DGL). In the present study, we examine how aging modulates the PLD, PAP, and DGL isoforms in cerebellar subcellular fractions from 4- (adult), 28-, and 33-mon-old (aged) rats. PI-4,5-bisphosphonate (PIP2)-dependent PLD, PAP1, and DGL1 were distributed in different percentages in all cerebellum subcellular fractions. On the other hand, PAP2 and DGL2 activities were observed in all subcellular fractions except in the cytosolic fraction. Aging modified the enzyme distribution pattern. In addition, aging decreased nuclear (45%), mitochondrial-synaptosomal (55%), and cytosolic (71%) PAP1 activity and increased (28%) microsomal PAP1 activity. DGL1 activity was decreased in nuclear (85%) and mitochondrial-synaptosomal (63%) fractions by aging. On the other hand, PIP2-dependent PLD activities were increased in the mitochondrial-synaptosomal fraction. PAP2 and DGL2 were increased in the microsomal fraction by 87 and 114%, respectively, and they were decreased in the nuclear fraction. The changes observed in cerebellum PAP1 and DGL1 activities from aged rats with respect to adult rats could be related to modifications in lipid metabolism. Differential PA metabolization during aging through PIP2-dependent PLD/PAP2/DGL2 activities could be related to alterations in the neural signal transduction mechanisms.
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PMID:Phospholipase D and phosphatidate phosphohydrolase activities in rat cerebellum during aging. 1555 54

The elongated form of conjugated linoleic acid (CLA), conjugated eicosadienoic acid (CEA, conj. 20:2delta(c11,t13/t12,c14)), was generated from CLA by liver microsomal fractions. Subsequent testing showed that dietary CEA significantly reduced body fat, and increased lean mass similar to CLA when compared to controls. CEA also decreased lipoprotein lipase activity and triacylglyceride, and increased glycerol release in 3T3-L1 adipocytes, correlated with the trans-12,cis-14 isomer, but CEA required a longer incubation period than cells treated with CLA. Based on the fact that CEA fed animals had CLA in tissue, we suggest that the effect of CEA is due to the CLA converted from CEA in the system. The delta-6 desaturated and elongated form of trans-10,cis-12 CLA (conjugated eicosatrienoic acid, CETA, conj. 20:3delta(c8,t12,c14)) inhibited LPL activity and increased glycerol release but was less active than trans-10,cis-12 CLA or CEA. The 21-carbon conjugated fatty acid, conjugated heneicosadienoic acid (CHDA, conj. 21:2delta(c12,t14/c13,t15)), was not active on LPL inhibition, triacylglyceride, or glycerol release in 3T3-L1 adipocytes. We also provide evidence that CLA was metabolized to conjugated dodecadienoic acid (conj. 12:2delta(c3,t5/t4,c6)). In addition, there were indications of the presence of conjugated tetradecadienoic acid (conj. 14:2delta(c5,t7/t6,c8)), suggesting that CLA can be metabolized through fatty acid beta-oxidation. This is the first work to report the presence of conjugated 12 and 14 carbon fatty acids, originated from CLA, and the biological activities of CEA, CETA and CHDA.
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PMID:Biological activities of conjugated fatty acids: conjugated eicosadienoic (conj. 20:2delta(c11,t13/t12,c14)), eicosatrienoic (conj. 20:3delta(c8,t12,c14)), and heneicosadienoic (conj. 21:2delta(c12,t14/c13,t15)) acids and other metabolites of conjugated linoleic acid. 1570 60

Phospholipase Cbeta3 (PLCbeta3) and PLCbeta4 are the two major isoforms in cerebellar Purkinje cells (PCs), displaying reciprocal expression across the cerebellum. Here, we examined subcellular distribution of PLCbeta3 in the mouse cerebellum by producing specific antibody. PLCbeta3 was detected as a particulate pattern of immunostaining in various PC elements. Like PLCbeta4, PLCbeta3 was richly distributed in somatodendritic compartments, where it was colocalized with molecules constituting the metabotropic glutamate receptor (mGluR1) signalling pathway, i.e. mGluR1alpha, G alpha q/G alpha 11 subunits of G q protein, inositol 1,4,5-trisphosphate receptor IP3R1, Homer1, protein kinase C PKCgamma, and diacylglycerol lipase DAGLalpha. Unlike PLCbeta4, PLCbeta3 was also distributed at low to moderate levels in PC axons, which were intense for IP3R1 and PKCgamma, low for G alpha q/G alpha 11, and negative for mGluR1alpha, Homer1, and DAGLalpha. By immunoelectron microscopy, PLCbeta3 was preferentially localized around the smooth endoplasmic reticulum in spines, dendrites, and axons of PCs, and also accumulated at the perisynapse of parallel fibre-PC synapses. Consistent with the ultrastructural localization, PLCbeta3 was biochemically enriched in the microsomal and postsynaptic density fractions. These results suggest that PLCbeta3 plays a major role in mediating mGluR1-dependent synaptic transmission, plasticity, and integration in PLCbeta3-dominant PCs, through eliciting Ca2+ release, protein phosphorylation, and endocannabinoid production at local somatodendritic compartments. Because PLCbeta3 can be activated by G betagamma subunits liberated from Gi/o and Gs proteins as well, axonal PLCbeta3 seems to modulate the conduction of action potentials through mediating local Ca2+ release and protein phosphorylation upon activation of a variety of G protein-coupled receptors other than mGluR1.
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PMID:Phospholipase Cbeta3 is distributed in both somatodendritic and axonal compartments and localized around perisynapse and smooth endoplasmic reticulum in mouse Purkinje cell subsets. 1729 1

Previous work conducted in our laboratory suggested a role for liver fatty acid-binding protein (L-FABP) in obesity that develops in aging female L-FABP gene-ablated (-/-) mice. To examine this possibility in more detail, cohorts of wild-type (+/+) and L-FABP (-/-) female mice were fed a standard, low-fat, nonpurified rodent diet for up to 18 mo. Various obesity-related parameters were examined, including body weight and fat and lean tissue mass. Obesity in (-/-) mice was associated with increased expression of nuclear receptors that induce PPARalpha (e.g. hepatocyte nuclear factor 1alpha, genotype effect) and of PPARalpha-regulated proteins involved in uptake of free (lipoprotein lipase and fatty acid transport protein, genotype, and/or age effect) and esterified (scavenger receptor class B type 1, genotype effect) long-chain fatty acids (LCFA). Hepatic total lipid and neutral lipid levels were not affected by age or genotype, consistent with absence of gross and histologic steatosis. There was increased mRNA expression of liver proteins involved in LCFA oxidation [mitochondrial 3-oxoacyl-CoA thiolase (genotype effect) and butyryl-CoA dehydrogenase (genotype and/or age effect)], increased expression of LCFA esterification enzymes [glycerol-3-phosphate acyltransferase (age x genotype effect) and acyl-CoA:cholesterol acyltransferase-2 (genotype and/or age effect)], and increased expression of proteins involved in intracellular transfer and secretion of esterified LCFA [liver microsomal triacylglycerol transfer protein (genotype effect), serum apolipoprotein (apo) B (genotype or age effect), and liver apoB (age and age x genotype effect)]. The data support a working model in which obesity development in these mice results from shifts toward reduced energy expenditure and/or more efficient energy uptake in the gut.
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PMID:Liver fatty acid-binding protein gene-ablated female mice exhibit increased age-dependent obesity. 1880 93

Phosphatidic acid synthesis via diacylglycerol kinase and free fatty acid release via diacylglycerol lipase were investigated in rat brain subcellular fractions using membrane-bound [I-(14)C]arachidonoyl-diacylglycerol as substrate. Labeled diacylglycerol was generated by incubating brain membranes containing [I-(14)C]arachidonoyl-phosphatidylinositols in the presence of deoxycholate and Ca(2+). Incubation of the prelabeled synaptosomes enriched in [1-(14)C]arachidonoyl-diacylglycerols or incubation of brain subcellular fractions with heat-treated prelabeled membranes resulted in the release of free fatty acids from the diacylglycerols. When incubations were carried out in the presence of ATP, MgCl(2) and NaF, both free fatty acid release and conversion of diacylglycerols to phosphatidic acids were observed. The conversion of diacylglycerols to phosphatidate or their hydrolysis to free fatty acids were linear with time for at least 15 min. In three brain subcellular fractions examined, diacylglycerol kinase activity indicated a pH maximum of 7.4. The free fatty acid release was enhanced slightly by Ca(2+) (1 mM), but Ca(2+) (0.5-4 mM) in the presence of Mg(2+) (10 mM) was inhibitory to the diacylglycerol kinase reaction. Phosphatidate formation was also inhibited by an excessive amount of deoxycholate added to the incubation mixture. Among the brain subcellular fractions, diacylglycerol kinase was more active in synaptic vesicles and cytosol than in the microsomal fraction, whereas diacylglycerol lipase activity was higher in the cytosol fraction than in the membrane fractions. Upon washing the membranes by centrifugation, a substantial portion of the diacylglycerol kinase activity was removed after the first washing, whereas the diacylglycerol lipase activity remained essentially unchanged. The metabolic role of arachidonoyl-diacylglycerols in brain membranes in relation to the biosynthesis of phosphatidate and the release of arachidomic acid is discussed.
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PMID:Diacylglycerol kinase and lipase activities in rat brain subcellular fractions. 2049 49

Lipid lowering is established as a proven intervention to reduce atherosclerosis and its complications. Statins form the basis of care but are not able to treat all aspects of dyslipidaemia. Many novel therapeutic compounds are being developed. These include additional therapeutics for low-density lipoprotein cholesterol, for example, thyroid mimetics (thyroid receptor beta-agonists), antisense oligonucleotides or microsomal transfer protein inhibitors (MTPI); triglycerides, for example, novel peroxosimal proliferator activating receptors agonists, MTPIs, diacylglycerol acyl transferase-1 inhibitors and high-density lipoprotein cholesterol (HDL-C), for example, mimetic peptides; HDL delipidation strategies and cholesterol ester transfer protein inhibitors and modulators of inflammation, for example, phospholipase inhibitors. Gene therapy for specific rare disorders, for example, lipoprotein lipase deficiency using alipogene tiparvovec is also in clinical trials. Lipid-lowering drugs are likely to prove a fast-developing area for novel treatments as possible synergies exist between new and established compounds for the treatment of atherosclerosis.
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PMID:New lipid-lowering drugs: an update. 2234 Apr 47

Severe hypertriglyceridemia is associated with acute pancreatitis and can be a manifestation of lipoprotein lipase (LPL) deficiency. It is associated with a spectrum of disorders, ranging from heterozygous LPL deficiency allied with environmental factors to rare severe cases of homozygous LPL deficiency. The genes associated with reduced LPL activity include LPL, its cofactor apoC-2, a controlling protein apoA-5 and the LPL receptor GPI-HBP1. The effects of mutations are exacerbated by environmental factors such as diet, pregnancy and insulin resistance. Treatment of clinical LPL deficiency is by ultra-low-fat diet along with the use of fibrates, omega-3 fatty acids, niacin, statins and insulin-sensitizing therapies, depending on the extent of residual LPL activity. Novel therapies that target lipoprotein particle assembly through the antisense oligonucleotides or by interference with triglyceride-loading microsomal transport protein inhibitors offer new potential options for treating hypertriglyceridemia.
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PMID:Diagnosis and treatment of severe hypertriglyceridemia. 2245 82

Infection and inflammation induce important changes in lipid metabolism, which result in increased free fatty acids and triacylglycerol in plasma and altered high density lipoprotein (HDL) metabolism. Our aim was to elucidate whether hepatic lipid droplets (LDs) are involved in the adaptations of lipid metabolism to endotoxemia. We characterized the lipid content and several enzymatic activities in subcellular fractions and subpopulations of LDs from livers of mice 24h after lipopolysaccharide (LPS) treatment and analyzed the expression of key genes involved in lipid management. Endotoxemic mice showed lower lipid content in LDs with decreased molar fraction of cholesteryl ester and higher diacylglycerol/triacylglycerol ratio as compared to their controls. They also showed a decrease in cytosolic triacylglycerol hydrolase activity, specifically in dense LDs, and in microsomal and cytosolic diacylglycerol hydrolase activity; concomitantly neutral lipid biosynthetic capacity and triacylglycerol levels in plasma lipoproteins increased. Together with the overexpression of genes involved in lipogenesis and HDL formation our results suggest that altered hepatic management of LD lipids in LPS-treated mice might be related to the channeled mobilization of triacylglycerol for very low density lipoprotein assembly and to the induction of cholesterol export.
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PMID:Involvement of lipid droplets in hepatic responses to lipopolysaccharide treatment in mice. 2366 17


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