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 liver plays a central role in lipid metabolism and plasma lipoprotein homeostasis. This dynamic process is regulated by a variety of liver-derived proteins. However, the specific liver cells that express these proteins are largely unknown. In the current study we measured mRNA levels for 13 genes encoding proteins involved in lipid metabolism in isolated rabbit hepatic parenchymal and nonparenchymal cells. For these analyses we cloned partial rabbit cDNAs for apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), apolipoprotein E (apoE), cholesteryl ester transfer protein (CETP), hepatic lipase (HL), lipoprotein lipase (LPL), HMG-CoA reductase, LDL-receptor, 7 alpha-hydroxylase, albumin, bile salt-dependent cholesteryl ester hydrolase (CEH), lecithin:cholesterol acyl transferase (LCAT), and plasminogen activator inhibitor protein-1 (PAI-1). The cDNAs provided the basis for developing quantitative RNAse protection assays for each mRNA. These assays were used to determine whether differential patterns of mRNA expression existed between liver and other tissues and between hepatic parenchymal and nonparenchymal cells. The data demonstrate a diverse range in tissue distribution and mRNA abundance. Liver expressed all mRNAs except for LPL and CEH. Messenger RNA levels in isolated liver cell populations normalized to total RNA revealed a cell segregation pattern for hepatic gene expression: parenchymal cells showed higher levels of apoA-I, apoB, apoE, albumin, LCAT, HL, and 7 alpha-hydroxylase mRNAs compared to nonparenchymal cells while nonparenchymal cells showed higher levels of CETP, LDL-receptor, HMG-CoA reductase, and PAI-1 mRNAs compared to parenchymal cells. These data demonstrate the existence of differential mRNA expression patterns in rabbit liver cell populations for genes encoding proteins affecting lipid metabolism.
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PMID:Hepatic expression of genes regulating lipid metabolism in rabbits. 826 14

The mechanism behind the hypolipidemic effect of the sulfur-substituted non-beta-oxidizable fatty acid analogue 1,10 bis(carboxymethylthio)decane, also known as 3-thiadicarboxylic acid, was studied in normolipidemic rats. Treatment with 3-thiadicarboxylic acid markedly decreased plasma levels of free fatty acids, triglycerides, and cholesterol. This was accompanied by a corresponding reduction in very low density lipoprotein (VLDL)-triglyceride and low density lipoprotein (LDL)-cholesterol levels (by 46% and 42%, respectively), whereas the decrease in high density lipoprotein (HDL)-cholesterol levels was less pronounced (16%). However, the composition of the various plasma lipoprotein fractions was essentially unchanged. Fatty acid oxidation in both mitochondria and peroxisomes was stimulated in parallel; the activities of ATP:citrate lyase and fatty acid synthase, two key enzymes in fatty acid synthesis, were inhibited. Hepatic triglyceride biosynthesis was retarded, as indicated by a decrease in the liver triglyceride content along with a 30% reduction of hepatic VLDL-triglyceride secretion. This was accompanied by a 50% inhibition of phosphatidate phosphohydrolase. The activities of plasma lipoprotein lipase as well as hepatic lipase were somewhat higher (18%) in treated animals, suggesting a slight increase in the clearance potential of triglyceride-rich lipoproteins. The cholesterol-lowering effect was accompanied by a considerable reduction (75%) in HMG-CoA reductase activity and a less pronounced inhibition of cholesterol 7 alpha-hydroxylase (52%), and acyl-CoA:cholesterol acyltransferase (25%) activities. The present data suggest that the hypotriglyceridemic and hypocholesterolemic properties of sulfur-substituted fatty acid analogues are primarily due to effects on triglyceride and cholesterol synthesis.
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PMID:On the mechanism of the hypolipidemic effect of sulfur-substituted hexadecanedioic acid (3-thiadicarboxylic acid) in normolipidemic rats. 837 Oct 65

The cyclic imides, o-(N-phthalimido)acetophenone, 2,3-dihydrophthazine-1,4-dione and N(4-methyl phenyl)diphenimide, were evaluated for their effects on bile lipids, bile acids, small intestinal absorption of cholesterol and cholic acid and liver and small intestinal enzyme activities involved in lipid metabolism. The agent at 20 mg/kg/day orally elevated rat bile excretion of lipids, e.g. cholesterol and phospholipids, and increased the bile flow rate. These agents altered the composition of the bile acids, but there was no significant increase in lithocholic acid which is most lithogenic in rats. The three agents did decrease cholesterol and cholic acid absorption from isolated in situ intestinal duodenum loops in the presence of drug. Hepatic and small intestinal mucosa enzyme activities, e.g. ATP-dependent citrate lyase, acyl CoA cholesterol acyl transferase, cholesterol-7-alpha hydroxylase, sn-glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase, and lipoprotein lipase were reduced. However, the cyclic imides did not accelerate HMG-CoA reductase activity, the regulatory enzyme for cholesterol synthesis, in a manner which would accelerate biliary cholesterol excretion. There was no evidence of hepatic cell damage afforded by the drugs based on clinical chemistry values which would induce alterations in bile acid concentrations after treatment of the rat.
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PMID:The effects of cyclic imides on lipid absorption from the intestine and on bile lipids and bile acids of Sprague Dawley rats. 847 58

Administration of nicotine to rats resulted in increased concentration of cholesterol, phospholipids and triglycerides in the serum and tissues. HDL cholesterol decreased while the LDL + VLDL cholesterol increased. There was increased tissue cholesterogenesis as evident from the increased activity of HMG-CoA reductase and increased incorporation into tissue unesterified cholesterol. Increased triglyceride synthesis in the tissues was evident from the increased activity of lipogenic enzymes and increased incorporation of label. Hepatic degradation of cholesterol to bile acids was decreased. The uptake of circulating triglyceride rich lipoproteins (chylomicrons and VLDL) was also decreased as revealed by the decreased activity of extrahepatic lipoprotein lipase. Plasma LCAT activity also showed a decrease in the rats given nicotine. The changes produced in the metabolism of lipids on nicotine administration were thus similar to those observed on exposure of rats to cigarette smoke, and it is felt that nicotine may therefore contribute at least partly to the risk posed by cigarette smoking in the development of atherosclerosis.
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PMID:Effect of nicotine administration on lipid metabolism in rats. 849 91

Dyslipidaemia may be treated with a number of safe and effective pharmacological agents that target specific lipid disorders through a variety of mechanisms. The bile-acid sequestrants--cholestyramine and colestipol--primarily decrease LDL cholesterol by binding bile acids, thereby decreasing intrahepatic cholesterol, and by increasing the activity of LDL receptors. Nicotinic acid lowers LDL cholesterol and triglyceride by decreasing VLDL synthesis and by decreasing free fatty acid mobilization from peripheral adipocytes. The HMG-CoA reductase inhibitors--fluvastatin, lovastatin, pravastatin and simvastatin--lower LDL cholesterol by partially inhibiting HMG-CoA reductase (the rate-limiting enzyme of cholesterol biosynthesis) and by increasing the activity of LDL receptors. The fibric-acid derivatives--bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil--primarily decrease triglyceride by increasing lipoprotein lipase activity and by decreasing the release of free fatty acids from peripheral adipose tissue. Probucol decreases LDL cholesterol by increasing non-receptor-mediated LDL clearance; as an anti-oxidant, probucol also decreases LDL oxidation; oxidized LDL which is thought to lead to atherogenesis. Although these agents have been proven safe in clinical trials, like any drug, they carry the risk for adverse effects. The bile-acid sequestrants may cause constipation, reflux oesophagitis, and dyspepsia, and may bind coadministered medications such as digitalis glycosides, beta blockers, warfarin, and exogenous thyroid hormone. Nicotinic acid use is commonly associated with flushing and pruritus and may also cause non-specific gastrointestinal complaints, hepatotoxicity (hepatic necrosis, hepatitis, or elevated liver enzymes), gout, myolysis, decreased glucose tolerance and increased fasting glucose levels, and ophthalmological complications including decreased visual acuity, toxic amblyopia, and cystic maculopathy. The HMG-CoA reductase inhibitors may produce liver enzyme elevations, creatine kinase elevations and rhabdomyolysis. The combination of a reductase inhibitor and a fibrate increases the risk for rhabdomyolysis. Possible adverse effects of the fibric-acid derivatives include abdominal discomfort, nausea, flatulence, increased lithogenicity of bile, liver enzyme elevations and creatine kinase elevations. Probucol may increase the QTc interval and may cause non-specific gastrointestinal complaints.
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PMID:Currently available hypolipidaemic drugs and future therapeutic developments. 859 27

Oral contraceptives (OC) have been shown to enhance the risk of atherosclerosis. In the present study we sought to determine which component of the OC (containing 0.067 mg estrogen and 0.667 mg of progestin) counts for alteration in lipids profile. Female rats were administered with 0.067 mg of 17 beta-estradiol and 0.667 mg of norethindron acetate/kg body weight. Estrogen treatment exhibited higher levels of lipids in the serum and tissues. LDL-cholesterol increased by three folds but HDL-cholesterol decreased significantly, while progestin group showed decreased levels of lipids and LDL cholesterol. Elevated hepatic cholesterogenesis was observed as indicated by increased activity of HMG-CoA reductase and elevated incorporation of labelled acetate into liver cholesterol in estrogen group. On the other hand, progestin treatment did not alter the activity of HMG-CoA reductase and the rate of incorporation of labelled acetate into hepatic cholesterol. Hepatic degradation of cholesterol to bile acids however, decreased with estrogen treatment. No considerable changes were observed in hepatic bile acid levels in progestin group. Release of lipoprotein into circulation increased but their clearance from the circulation decreased as revealed by the activity of lipoprotein lipase (LPL) of extrahepatic tissues in estrogen group. With progestin treatment, activity of LPL increased significantly in adipose tissue. Activity of hepatic malic enzyme and glucose 6-phosphate dehydrogenase enhanced considerably in estrogen group, while activities of these enzymes were depressed with progestin administration. Thus results indicate that estrogen component of oral pills counts for major changes in lipid and lipoprotein metabolism favouring the development of atherosclerosis.
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PMID:Influence of components of oral contraceptive on lipid metabolism. 864 14

A series of 3-amino-1-(2,3,4-mononitro-, mono-, or dihalo-phenyl)propan-1-ones were synthesized and shown to be effective in lowering both serum cholesterol and triglyceride levels significantly in CF1 mice and Sprague-Dawley rats. All analogs showed better activity than the standard drugs, lovastatin and clofibrate, in reducing the serum cholesterol and triglyceride levels in mice at 8 mg/kg/day intraperitoneally. The best active analogs, 3-morpholino-1(3-nitrophenyl)propan-1-one (4) and 3-piperidino-1-(3-nitrophenyl)propan-1-one (5), exhibited 58% and 67% reduction of serum cholesterol levels, respectively, and 42% and 46% reduction of serum triglyceride levels, respectively, after 16 days of administration at 8 mg/kg/day intraperitoneally in CF1 mice. In Sprague-Dawley rats at 8 mg/kg/day oral administration, both compounds (4 and 5) significantly decreased the serum cholesterol and triglyceride levels. Rat tissue lipid levels were reduced significantly by compound 4, while less effects resulted from compound 5. The cholesterol and triglyceride levels in chylomicrons, VLDL, and LDL fractions were reduced by both analogs while the HDL cholesterol levels were significantly increased. Compound 5 was also effective in lowering serum cholesterol and triglyceride levels in hyperlipidemic mice, at 8 mg/kg/day intraperitoneally, but not effective in hyperlipidemic rats at 8 mg/kg/day orally. Cholesterol and triglyceride lowering effects of the agents were correlated with inhibition of the activities of liver acetyl CoA synthetase, HMG CoA reductase, phosphatidylate phosphohydrolase, and lipoprotein lipase, and with elevation of the activity of cholesterol ester hydrolase.
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PMID:Hypolipidemic activity of 3-amino-1-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-1-ones in rodents. 876 82

If dietary therapy and other lifestyle changes do not adequately normalise blood lipid levels, lipid-regulating drugs, as single-drug or combination-drug therapy, may be prescribed to supplement lifestyle changes. Evaluation of the individual patient's health and risk status, determination of the dyslipidaemia, definition of treatment goals and a clear understanding of the mechanisms and effects of lipid-regulating agents are necessary for optimisation of treatment. Although all the available lipid-regulating agents lower low density lipoprotein (LDL) cholesterol, the agents with the greatest LDL cholesterol-lowering effect are the bile acid sequestrants, which up-regulate the LDL receptor by the decrease in intrahepatic cholesterol caused by the interruption of enterohepatic circulation of cholesterol-rich bile acids, and the HMG-CoA reductase inhibitors, which partially inhibit HMG-CoA reductase. The agents with the greatest triglyceride-lowering effect are nicotinic acid, which decreases the production of very low density lipoprotein (VLDL) cholesterol and reduces the availability of free fatty acids in the circulation, and the fibric acid derivatives, which increase lipoprotein lipase activity and may also decrease the release of free fatty acids. Although the safety profile of the available lipid-regulating drugs has been established, patients should be monitored for potential adverse effects and interactions with concomitantly administered agents. When used correctly, lipid-regulating drug therapy is highly effective in the treatment of a variety of dyslipidaemias.
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PMID:Choosing the right lipid-regulating agent. A guide to selection. 911 15

We are attempting to develop a chemically-induced murine model for the study of atherosclerosis. Injection of poloxamer-407 (P-407) into rats and mice causes significant dose-dependent hypercholesterolemia and hypertriglyglyceridemia. The elevated triglycerides (TG) seem to result primarily from the compound's inhibition of lipoprotein lipase. P-407 also indirectly stimulates the activity of the rate limiting enzyme in cholesterol (CHOL) biosynthesis, HMG CoA reductase. In addition, P-407 promotes changes in the concentration of hepatic CHOL content. These date indicate that the hyper CHOL could be the result of increased CHOL synthesis, as well as a clearing of CHOL from the liver. Chronic injection into mice of P-407 for 145 d produced atherogenic lesions in the aortas of C57BL/6 mice. The response was equivalent to that seen in animals eating a high CHOL diet for 145 d. Cholic acid potentiated the P-407-induced atherogenesis. These data suggest that P-407 could be used as an agent for the study of hyperlipidemia-induced atherogenesis.
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PMID:The poloxamer 407-induced hyperlipidemic atherogenic animal model. 937 76

Beginning with the description of clofibrate in 1962, derivatives of fibric acid (fibrates) have been used clinically to treat dyslipidaemias. Subsequently, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate and long-acting forms of gemfibrozil, fenofibrate and bezafibrate have been developed. Clinically, this class of drugs appears to be most useful in lipoprotein disorders characterised by elevations of very low density lipoprotein and plasma triglycerides, which are often accompanied by reductions in high density lipoprotein (HDL) levels. The principal effects are a reduction in triglyceride and increase in HDL levels, with increases in the activity of hepatic lipase and lipoprotein lipase. There is some reduction of low density lipoprotein (LDL), lipoprotein (a), fibrinogen and uric acid. As a class, these drugs are generally well absorbed from the gastrointestinal tract (immediate-acting fenofibrate being the exception) and display a high degree of binding to albumin. Fibrates are metabolised by the hepatic cytochrome P450 (CYP) 3A4. All members of this class are primarily excreted via the kidneys and display some increase in plasma half-life in individuals with severe renal impairment. The long-acting forms of gemfibrozil and bezafibrate have pharmacokinetic properties similar to those of their immediate-acting parent compounds. The long-acting form of fenofibrate, produced by the process of micronisation, has increased oral bioavailability with less variability in absorption compared with the immediate-acting form of fenofibrate. Drug interactions are seen with other drugs that share a high degree of binding to albumin or are metabolised by CYP3A4. Clinically the most important and most commonly reported drug interactions are with HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin and fluvastatin), warfarin, cyclosporin and oral hypoglycaemic agents [including metformin, tolbutamide and glibenclamide (glyburide)]. The main potential for drug interactions is with drugs or compounds that are metabolised by or affect CYP3A4, including imidazoles, grapefruit juice, erythromycin, mibefradil and others.
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PMID:Clinical pharmacokinetics of fibric acid derivatives (fibrates). 951 85


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