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)

A series of cyclic imides, which possess a bulkier N-ring structure than phthalimide and saccharin, were shown to suppress LDL receptor binding, internalization and degradation of isolated rat hepatocytes, foam cells, human fibroblasts and mouse macrophages. The HDL receptor binding and internalization was accelerated in hepatocytes but not in other tissue types. In general, the HDL receptor activity and degradation was reduced by the cyclic imides. The in vivo studies with selected cyclic imides supported this finding in that 125I-LDL was not cleared from serum as rapidly as the control after 14 days of treatment, whereas 125I-HDL was cleared more rapidly by treated rats. The tissue uptake of 125I-LDL amd 125I-HDL was generally reduced in the treated rat tissues after 14 days dosing. These agents did not suppress HMG-CoA reductase activity in any of the tissue cell lines. A correlation existed between lower LDL receptor activity and stimulated HMG-CoA reductase activity in cells. The cyclic imides suppressed the activities of acyl-CoA cholesterol-acyltransferase, sn-glycerol-3-phosphate acyl transferase, and heparin-induced tissue lipoprotein lipase. Neutral cholesterol ester hydrolase activity and protein synthesis were markedly stimulated by the cyclic imides in the aorta foam cells, but not the other cell types.
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PMID:The effects of cyclic imides on lipoprotein receptor binding and degradation of rat and human cells and effects on regulatory enzymes of lipid metabolism. 132 61

Hypolipemic drugs decrease the plasmatic concentrations of atherogenic lipoproteins, especially LDL. Two main drug families are used: fibrates and inhibitors of HMG CoA reductase. Fibrates act essentially as an activator of lipoprotein lipase and by increasing the catabolism of triglyceride rich lipoproteins. Further, they have a slight and non specific inhibitory effect on HMG CoA reductase activity, while, the new drug family of "statines" have a high, specific inhibitory effect on this essential enzyme of the cholesterol synthesis pathway. This enzymatic inhibition decreases the cholesterol synthesis and increases the activity of the hepatic LDL receptors, which are in charge of LDL elimination from the body. Resins entrap biliary salts and increase the cholesterol loss in feces and induce an over expression of the LDL receptors of the hepatocytes. Probucol inhibits atherogenesis by decreasing both LDL and HDL cholesterol and delaying LDL oxidative processing which is now believed to be one of the major factors of atherogenicity.
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PMID:[Mechanism of action of hypolipemic drugs]. 140 1

Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase have been approved for treatment of hypercholesterolemia in humans. This class of therapeutic agents, in addition to lowering plasma cholesterol, reduces plasma triglyceride levels. We have investigated the mechanism of triglyceride-lowering effect of lovastatin in the hypertriglyceridemic state by using a rodent model of hypertriglyceridemia and obesity, the Zucker obese (fa/fa) rat. Lovastatin treatment (4 mg/kg), as compared to placebo, caused a 338% reduction in plasma triglyceride (146 +/- 5 vs. 494 +/- 76 mg/dl), a 58% decrease in total cholesterol (99 +/- 13 vs. 156 +/- 18 mg/dl), and a 67% reduction in high density lipoprotein (HDL)-cholesterol (69 +/- 8 vs. 115 +/- 15 mg/dl). The fall seen in plasma triglyceride was due to a decrease in hepatic secretion of very low density lipoproteins (VLDL), determined after blocking the clearance of triglyceride-rich lipoproteins with Triton WR-1339. Lovastatin treatment did not affect either the activities of hepatic lipogenic enzymes, glucose-6-phosphate dehydrogenase, or malic enzyme, or the activities of the lipolytic enzymes of adipose tissue, lipoprotein lipase, or liver, hepatic triglyceride lipase. Supplementation of mevalonolactone in the diet partially reversed the changes in plasma triglyceride (265 +/- 37 vs. 146 +/- 5 mg/dl), but not in total or HDL-cholesterol. These data demonstrate that, in the hypertriglyceridemic Zucker rat model, HMG-CoA reductase inhibitors reduce the rate of secretion of VLDL and this effect can be partially reversed by administration of mevalonolactone.
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PMID:Mechanisms of triglyceride-lowering effect of an HMG-CoA reductase inhibitor in a hypertriglyceridemic animal model, the Zucker obese rat. 155 26

Dyslipidemia of chronic renal failure is of multifactorial origin. Decreased activity of lipoprotein lipase and hepatic triglyceride lipase, peripheral insulin resistance, hyperparathyroidism and L-carnitine deficiency are the contributing factors. This results in a disturbed catabolism of chylomicron, accumulation of very-low-density (VLDL) and intermediate-density (IDL) lipoproteins as well as incompletely cleared remnant particles, whereas low-density lipoprotein (LDL) levels are diminished. There is current debate as to whether cardiovascular disease is accelerated and whether hyperlipidemia should specifically be treated. In addition, there have been few means of influencing these metabolic alterations. Drug incompatibility and consequently side effects render treatment difficult. The drugs that have been most tested for lipid lowering in chronic renal failure are the fibric acids. By their mode of action, they are the logical choice. Dose reduction overcomes major side effects such as myopathy and rhabdomyolysis. The second generation of fibric acid derivatives (gemfibrozil and beclobrate) show several advantages over formerly used derivatives. Treatment with lovastatin and simvastatin appears to be safe and is recommended in a minority of patients with predominantly elevations of LDL. HMG-CoA reductase inhibitors also lower remnant particles effectively in hemodialysis (HD) patients. L-Carnitine and low-molecular-weight heparin have been shown to influence VLDL rich in triglycerides in a subset of patients on HD. In posttransplant hyperlipidemia, diet remains the first course of action in all patients. When this approach fails, the new lipid-lowering agents, especially fibric acids, appear to be safe in short-term studies in azathioprine- and ciclosporin-treated patients. Lovastatin has been shown to be safe in stable renal transplant patients. Its toxicity seems to depend mainly on high ciclosporin whole blood through or plasma levels.
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PMID:Hyperlipoproteinemia in chronic renal failure: pathophysiological and therapeutic aspects. 186 98

Fibric acid derivatives (FADs) are a class of drugs that have been shown to reduce the production of very low-density lipoprotein (VLDL) while enhancing VLDL clearance due to the stimulation of lipoprotein lipase activity. The drugs can reduce plasma triglyceride levels while raising high-density lipoprotein (HDL) cholesterol levels. Their effects on low-density lipoprotein (LDL) cholesterol levels are less marked and more variable. There is evidence that oral gemfibrozil (Lopid, Parke-Davis, Morris Plains, NJ) can reduce the risk of serious coronary events, specifically in those patients who had elevations of both LDL cholesterol levels and total plasma triglyceride levels with lower HDL cholesterol levels. Newer FADs (bezafibrate, ciprofibrate, fenofibrate) have been shown to have greater efficacy in reducing LDL cholesterol than gemfibrozil but, in general, these drugs are not as effective as the other primary drugs used to lower LDL levels. The FADs are also used to treat adult patients with very high levels of triglycerides who have pancreatitis and whose disease cannot be managed with dietary therapy. The FADs are well tolerated, with dyspepsia and abdominal pain the most common adverse effects. A small risk of cholelithiasis exists with these drugs, and caution should be used when combining these drugs with HMG-CoA reductase inhibitors because the combination increases the incidence of hyperlipidemic myositis and rhabdomyolysis.
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PMID:Effects of gemfibrozil and other fibric acid derivatives on blood lipids and lipoproteins. 204 26

Rats administered estrogen-progestin formulation (0.667 mg of synthetic progestin and 0.067 mg of synthetic estrogen/kg body wt) showed increased hepatic cholesterogenesis, as evidenced by an increased activity of HMG-CoA reductase and increased incorporation of labelled acetate into liver cholesterol. Hepatic degradation of cholesterol to bile acids, however, was decreased. There was increased release of lipoproteins into the circulation but their clearance from the circulation was lower as revealed by a decreased activity of lipoprotein lipase of the extrahepatic tissues. Activity of plasma LCAT, which is involved in the transport of cholesterol from the tissues, was also decreased. The increase in serum and aortic cholesterol levels, increase in LDL cholesterol and decrease in HDL cholesterol in rats administered estrogen-progestin formulation suggest that prolonged administration of this formulation may predispose towards atherosclerosis.
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PMID:Mechanism of hyperlipidemia produced by estrogen-progestin formulation. 207 Nov 84

Hyperlipidemia is common in patients with glomerular proteinuria. It may contribute to atherosclerotic complications and accelerate glomerular damage. Early trials of the fibric acid derivative clofibrate led to a myositis syndrome causing many nephrologists to abandon attempts at treatment of nephrotic hyperlipidemia. Recent trials with lipid-lowering medications have been successful without major side effects. The bile acid sequestrants colestipol and cholestyramine bind bile acids in the gut and deplete the hepatic cholesterol pool, thus inducing LDL hepatocyte receptors. Recent studies showed a reduction of total cholesterol of 8-20% and LDL cholesterol of 19-31% without significant changes in HDL cholesterol. Probucol has reduced total cholesterol 23-30% and LDL cholesterol 23-25% in nephrotic patients. Although HDL cholesterol was reduced, the LDL/HDL ratio remains favorably changed. The fibric acid derivative gemfibrozil inhibits adipose lipolysis and enhances lipoprotein lipase activity thus decreasing LDL synthesis and increasing its removal. It caused a large decrease in triglycerides with a 13-15% decrease in total and LDL cholesterol in a recent trial. HDL cholesterol increased 18%. The HMG-CoA reductase inhibitors inhibit the rate-limiting step in cholesterol biosynthesis hence inducing an increase in LDL receptors on hepatocytes. Trials have shown decreases of 18-36% in total cholesterol and 18-47% in LDL cholesterol, while HDL cholesterol was either increased or unchanged. The use of lipid-lowering agents of several classes has been effective in ameliorating the progression of glomerular damage in a number of different models of glomerulosclerosis. Nevertheless, so far in humans lipid lowering drugs have not been established to have an effect on either the degree of proteinuria or the progression of glomerulosclerosis.
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PMID:Lipid-lowering agents in proteinuric diseases. 225 70

The aim of this study was to characterize the plasma lipoprotein pattern and some aspects of cholesterol metabolism in a line of hyperlipemic male rats. Plasma cholesterol and triglycerides were increased about 3-fold as compared to control animals (238 vs. 75 and 185 vs. 59 mg/dl respectively). The plasma lipoprotein distribution and the chemical composition of the isolated lipoproteins was unaffected. Plasma triglyceride production rate was increased (40%, P less than 0.01) and post-heparin lipoprotein lipase activity in plasma decreased (-28%, P less than 0.01) in the hyperlipemic rat. The activity of 3 enzymes involved in cholesterol metabolism (HMG-CoA reductase, cholesterol 7 alpha-hydroxylase, and acyl-CoA cholesterol-acyltransferase) did not differ from control values. 3H2O incorporation into digitonin-precipitable sterols, however, was significantly higher than in controls. This finding was due, in part, to an increased liver weight in the hyperlipemic animals. Furthermore kinetic data using 125I-LDL showed that the fractional catabolic rate of lipoprotein was within the normal range, while the synthetic rate of LDL protein was increased (0.67 vs. 0.3 mg/kg/h, P less than 0.01) in the hyperlipemic rat. These observations suggest that multiple metabolic defects underline the hyperlipemia observed in this animal model.
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PMID:Plasma lipoproteins and cholesterol metabolism in spontaneously hyperlipemic rats. 273 Jul 13

The hypolipidemic agents, phthalimide, saccharin, o-(N-phthalimido) acetophenone, N-(p-chlorobenzoyl) sulfamate, and o-chlorobenzylsulfonamide affected low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptor activity and lipoprotein degradation. In isolated rat hepatocytes, rat aorta foam cells, and human fibroblasts, LDL receptor activity, which is dependent on apo-B and -E, was inhibited by the drugs in a dose-dependent manner. LDL degradation was accelerated in the hepatocytes, while it was inhibited in aorta cells and fibroblasts. The drugs enhanced HDL receptor activity, dependent on apo-E and -A1, and HDL degradation in the hepatocytes, whereas in fibroblasts and aorta cells HDL receptor binding and degradation were suppressed. In parallel, activities of acyl CoA acyl transferase, sn-glycerol-3-phosphate acyl transferase, and heparin-induced lipoprotein lipase decreased and activities of HMG-CoA reductase and cholesterol oleate-ester hydrolase increased. In fibroblasts the presence of drugs enhanced HDL binding of intracellular cholesterol. In vivo studies demonstrated that phthalimide and saccharin treatment enhanced the clearance of HDL and decreased the clearance of LDL from the serum of rats. The results suggest that the mode of action of the agents is to modulate the lipoprotein receptor and, thereby, the clearance of lipids from peripheral tissue as part of the hypolipidemic activity.
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PMID:The effects of phthalimide and saccharin derivatives on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptor activity and related enzyme activities. 285 33

The mechanism of the hypolipidemic action of bezafibrate was investigated in rats. Bezafibrate decreased the incorporation of 14C-acetic acid into the liver and serum triglyceride and inhibited liver acetyl CoA carboxylate activity. Bezafibrate increased liver beta-oxidation, but it had no effect on lipolysis and triglyceride secretion from the liver. Bezafibrate accelerated the elimination of serum triglyceride in Intralipid injected rats and increased tissue lipoprotein lipase activity. Bezafibrate decreased the incorporation of 14C-acetic acid into liver cholesterol and inhibited liver HMG-CoA reductase activity. Bezafibrate had no effect on cholesterol absorption and excretion. These results suggest that the hypotriglyceridemic actions of bezafibrate are due to inhibition of triglyceride synthesis and acceleration of triglyceride elimination and that the hypocholesterolemic action of bezafibrate is mainly due to inhibition of liver HMG-CoA reductase activity.
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PMID:[Pharmacological investigation of bezafibrate, a hypolipidemic agent (2). Mechanism of the hypolipidemic action of bezafibrate in rats]. 290 2


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