Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested previously that lipoprotein lipase may act as a ligand to enhance binding and uptake of lipoprotein particles. In the present study we have examined the capacity of bovine milk lipoprotein lipase to induce intracellular accumulation of triglyceride and cholesterol ester by VLDL (Sr 60-400) isolated from Type IV hypertriglyceridemic subject (HTg-VLDL) in HepG2 cells, independent of its lipolytic activity. We have also attempted to elucidate the cellular receptor mechanisms responsible for these effects. HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester were dependent on the presence of an active lipase. Bovine milk lipoprotein lipase (LPL) increases triglyceride mass by 301% +/- 28% (P < 0.0005) and cholesterol ester mass by 176% +/- 12% (P < 0.0005). These HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester did not occur when heat-inactivated lipase was used. Rhizopus lipase could replace LPL and cause equivalent increases in intracellular triglyceride and cholesterol ester (472% +/- 61%(P < 0.005) and 202% +/- 25% (P < 0.025) respectively vs. control). HTg-VLDL treated with LPL and reisolated also caused equivalent increases (274% +/- 18%(P < 0.01) and 177% +/- 12% (P < 0.005) for triglyceride and cholesterol ester). LDL also caused increases in intracellular cholesterol ester (189% +/- 20%(P < 0.005)), although three times more LDL cholesterol had to be added to achieve the same effect. These LDL-induced increases were effectively blocked by monoclonal antibodies directed against the B,E receptor binding domains of apo B (-97% +/- 13% (P < 0.0005) with anti-apo B 5E11 and -68% +/- 13% (P < 0.05) for anti-apo B B1B3) or by anti-B,E receptor antibodies (-77% +/- 7% (P < 0.01) antibody C7). These same antibodies had little effect on the HTg-VLDL+LPL-induced increases in cholesterol ester (+21%, +15% and -22% for 5E11, B1B3 and C7, respectively). Monoclonal anti-apo E antibodies also had no effect on LDL-mediated increases in intracellular cholesterol ester, but had a small and significant effect on VLDL-mediated increases in cholesterol ester. However, heparin, which interferes with cell surface proteoglycan interaction, was very effective at blocking HTg-VLDL-mediated increases in cholesterol ester in the presence of LPL (-86% +/- 8% P < 0.0005). Heparin was also effective in the presence of Rhizopus lipase (-79%) or lipolyzed re-isolated HTg-VLDL (-95%). These results suggest that lipoprotein lipase may enhance the uptake process beyond its role in lipolytic remodelling but does not appear to be an absolute requirement. In contrast, heparin had no effect on LDL-mediated cholesterol ester accumulation. Lactoferrin, which inhibits interaction with the low density lipoprotein receptor-related protein (LRP), was also very effective at inhibiting HTg-VLDL increases in intracellular cholesterol ester (-95% +/- 6%, P < 0.01). However, there was no effect of either heparin or lactoferrin on HTg-VLDL-mediated triglyceride accumulation. Thus cell surface heparin sulphate may facilitate intracellular lipid acquisition by providing a stabilizing bridge with the lipoproteins and enhance uptake through receptor-mediated processes such as LRP.
Atherosclerosis 1996 Feb
PMID:Inhibition of lipoprotein lipase induced cholesterol ester accumulation in human hepatoma HepG2 cells. 864 51

Most measures taken to prevent atherosclerosis still aim at lowering the cholesterol content of the plasma lipoproteins by dietary and pharmacological means. This approach has only proved successful to a limited extent. Diseases secondary to atherosclerosis are still the commonest cause of death in western industrialized countries. As all metabolic processes are regulated by opposing processes of equilibrium, i.e. by processes directed towards performance and recovery, we asked ourselves whether the fatty degeneration and sclerosis of the arteries could be causally related to a continuous dysregulation of these processes. We consider this to be the case, with a continuous deficiency of glycosaminoglycans (heparin, heparinoids) on the endothelial surface of the vessels. Numerous studies indicate that in the case of thinning of the anionic glycosaminoglycan film on the endothelial surface, the lipoprotein-lipase and antithrombin III activity induced by heparin is reduced, as result of which hyperlipoproteinaemia and increased tendency to thrombosis can only by compensated for to an inadequate extent. The formation of glycosaminoglycans is a characteristic of all mesenchymal cells, whereby the exogenous introduction of glycosaminoglycans into the extracellular space is of decisive importance for adequate glycosaminoglycan synthesis. Since Engelberg reported outstanding results obtained with heparin injections in the prevention and treatment of atherosclerotic disorders of the cardiac circulation, we considered it appropriate to use the well-proven dietary supplement of glycosaminoglycans in rheumatology, in the treatment of arthrosis, as well as in the prevention and treatment of atherosclerosis.
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PMID:The pathogenesis and prevention of atherosclerosis. 895 6

Transgenic rabbits were produced that expressed high plasma levels (30-70 mg/dl) of human apolipoprotein (apo) E2(Cys-158), an apoE variant associated with the human genetic disorder type III hyperlipoproteinemia (HLP). Male transgenic rabbits fed normal chow had up to 8-fold (289 +/- 148 mg/dl) and 15-fold (697 +/- 452 mg/dl) increases in plasma total cholesterol and triglycerides, respectively, compared with nontransgenic males. Female transgenic rabbits had only a modest hyperlipidemia (total cholesterol, 140 +/- 46 mg/dl; total triglycerides, 174 +/- 66 mg/dl). Both sexes displayed the hallmarks fo type III HLP: beta-migrating very low density lipoproteins (beta-VLDL) (intestinal and hepatic remnant lipoproteins) and significantly increased VLDL and intermediate density lipoproteins. Apolipoprotein E2-containing VLDL particles were cleared from teh circulation more slowly and were more resistant to lipoprotein lipase-mediated lipolysis than normal VLDL. Only females had increased high density lipoproteins (HDL) (40%), which were shifted from typical small HDL to larger HDL1. Plasma apoE2 was predominantly associated with beta-VLDL in males and with HDL in females. To ascertain reasons for the phenotypic gender difference, we treated male transgenic rabbits with 17alpha-ethinyl estradiol. Estrogen treatment for 10 days dramatically decreased total cholesterol (73%) and triglycerides (89%) and converted beta-VLDL to pre-beta-migrating VLDL. Concomitantly, lipoprotein lipase and hepatic lipase activities increased by 90%, low density lipoprotein receptor activity was stimulated significantly, apoE2 was redistributed to HDL, and HDL were converted to HDL1. Conversely, ovariectomy in female transgenic rabbits significantly increased total cholesterol (75%), triglycerides (117%), and beta-VLDL, while decreasing lipoprotein lipase and hepatic lipase activities by 35% and redistributing apoE2 to the beta-VLDL. Thus, estrogen status appears to be responsible for much of the gender difference of the lipoprotein phenotype, mainly by modulating both lipase and low density lipoprotein receptor activities. Furthermore, transgenic rabbits fed normal chow for 11 months developed fatty streaks, and some had more advanced atherosclerotic lesions, especially around the aortic arch and proximal abdominal aorta. The lesions were more extensive in males, roughly correlating with the magnitude of the hyperlipidemia. Therefore, high plasma levels of human apoE2 in transgenic rabbits result in a type III HLP phenotype, in which males have both more severe hyperlipidemia and more extensive atherosclerosis than females.
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PMID:Apolipoprotein E2 transgenic rabbits. Modulation of the type III hyperlipoproteinemic phenotype by estrogen and occurrence of spontaneous atherosclerosis. 931 50

Bile salt-dependent lipase (BSDL, E.C. 3.1.1.-) is a digestive enzyme secreted by the pancreatic acinar cell. Once in the duodenum, the enzyme, upon activation by primary bile salts, hydrolyzes dietary lipid esters such as cholesteryl esters and lipid-soluble vitamin esters. This enzyme is partially transferred from the duodenum or pancreas to the circulation where it has been postulated to exert a systemic action on atheroma-generating oxidized-low density lipoprotein (LDL). In the present study, sera from 40 healthy normolipidemic volunteers were used to investigate the possible linkage between circulating BSDL, lipids, and lipoproteins. We showed, firstly, that pancreatic-like BSDL activity can be detected in these serums. Secondly, BSDL activity increased significantly with the level of LDL-cholesterol and was also positively linked to the serum concentration of Apo B100 and Apo A-I. Thirdly, we also established that BSDL was associated with LDL, in part by a specific interaction with Apo B100, while no interaction was found with Apo A-I. No linkage with other recorded parameters (triglycerides, phospholipids, and high density lipoprotein-cholesterol) was detected. Because an increase in LDL-cholesterol represents an important risk factor for atheroma, the concomitant increase in BSDL, which can metabolize atherogenic LDL, suggests for the first time that this circulating enzyme may exert a positive effect against atherosclerosis.
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PMID:Pancreatic bile salt-dependent lipase activity in serum of normolipidemic patients. 939 99

Lysosomal acid lipase (LAL) deficiency leads to two phenotypically different diseases: cholesteryl ester storage disease (CESD) and Wolman's disease. Lysosomal acid lipase hydrolyzes cholesteryl esters and triglycerides. Deficiency of LAL results in intralysosomal storage of cholesteryl esters and triglycerides. CESD has a chronic and benign course and is characterized by hepatomegaly and mild hypercholesterolemia. It leads to fibrosis (cirrhosis) and early atherosclerosis. This report presents the clinical, biochemical and microscopic data of seven patients with CESD followed up over 10 years. The physical development of all the study children remained within the normal range; 7 patients had hepatomegaly and 6 also had splenomegaly. Three patients had normal cholesterol, triglycerides and transaminases values; the other four had slightly elevated levels for these parameters. The activity of LAL in all patients was reduced to below 30% of the lower normal value. Histologically, cholesteryl crystals and lipid storage vacuoles in Kupffer cells were present in all examined patients except one. Accumulation of cholesteryl esters was visible on thin-layer chromatography of lipid extracts obtained from liver biopsies.
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PMID:Clinical, biochemical and histological analysis of seven patients with cholesteryl ester storage disease. 944 50

1. Pancreatic bile-salt-dependent lipase has been detected in human plasma where it has the capability to modify normal low- and high-density lipoprotein composition and structure and to reduce the atherogenicity of oxidized low-density lipoprotein (Shamir R, Johnson WJ, Morlock-Fitzpatrick K, Zolfaghari R, Li L, Mas E, Lombardo D, Morel DW, Fisher EA. Pancreatic carboxyl ester lipase: a circulating enzyme that modifies normal and oxidized lipoproteins in vitro. J Clin Invest 1996; 97: 1696-704). 2. In the present study, we investigated the effect of glycation and particularly that of human serum albumin on the activity of bile-salt-dependent lipase. In vitro, bile-salt-dependent lipase activity decreased in the presence of human serum albumin; however, this was less pronounced in the presence of glycated human serum albumin. In vivo, bile-salt-dependent lipase specific activity was about 2-fold higher in the sera of diabetic patients than in the sera of normal subjects. 3. A significant increase in the specific activity of bile-salt-dependent lipase related to the serum level of glycation was observed. The increase in bile-salt-dependent lipase specific activity was not related to the glucose concentration in serum suggesting that glycation of bile-salt-dependent lipase could not be involved in the observed effects. Although the stability of serum bile-salt-dependent lipase was important enough to allow a systemic action of the enzyme on lipoproteins, it could not explain the higher activity of the enzyme in diabetic serum. 4. We concluded that bile-salt-dependent lipase could be helpful against the premature development of atherosclerosis in diabetes.
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PMID:Pancreatic bile-salt-dependent lipase activity in serum of diabetic patients: is there a relationship with glycation? 953 27

Although the body status of zinc and copper in cardiovascular disease (CVD) has been shown to be important little is known about the effect of these trace element alterations on lipolytic enzyme activities in atherosclerosis human subjects. The aim of the present study was to evaluate the multiple relationships between lipase (GEH = glycerol ester hydrolase, EC 3.1.1.3) activity, zinc, copper and lipid concentrations in serum and the arterial wall of men with atherosclerosis obliterans (AO) and abdominal aortic aneurysm (AA). The mean concentrations of zinc and copper in serum were found to be higher in AO in comparison to AA. Low but significant correlation coefficients for zinc and lipase catalytic activity (r > or = 0.64) and lipase metabolic activity GEH/TAG (r > or = 0.67) were calculated in serum in AA. Multiple correlation coefficients (R) for three variables GEH-Zn-Cu were found to be significant for both AO and AA (R > or = 0.45 and 0.68, respectively) in serum but not in the arterial wall. Multiple relations for GEH/TAG-HDL-C (LDLC)-Zn(Cu) were found to be significant (R > or = 0.63) in serum in AA. The results indicate the influence of zinc and copper on the activity of lipase and lipid concentrations and suggest that the multiple relations may provide a better understanding of the role these elements play in atherosclerosis than relations between 2 substances.
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PMID:Serum glycerol ester hydrolase activity is related to zinc and copper concentrations in atherosclerosis obliterans and aneurysm. 963 11

The pivotal role of heparin-releasable lipases in the clearing of postprandial lipids is known for a long time. The hydrolysis of triglycerides under influence of lipoprotein lipase is among the first recognised and well defined processes in postprandial lipid metabolism. More recently, also hepatic lipase has been implicated in the clearing of postprandial lipoproteins. Lipoprotein lipase as well as hepatic lipase are also involved in the metabolism of several other lipoproteins. However, their capacity is limited. This may lead to interaction of different metabolic processes and competition for the available lipase by different lipoproteins. Indeed, it is generally accepted that the exaggerated postprandial response in subjects with hypertriglyceridemia is at least partially due to competition between endogenous (VLDL) and exogenous (chylomicrons) lipoproteins. Similar mechanisms may also take place in the liver where hepatic lipase plays a role in the metabolism of several lipoproteins. In this short review, the roles of lipoprotein lipase and hepatic lipase in postprandial lipoprotein metabolism are discussed in relation(s) to their suggested function in the metabolism of different lipoproteins.
Atherosclerosis 1998 Dec
PMID:Role of lipoprotein lipases in postprandial lipid metabolism. 988 39

The trapping of apolipoprotein (apo)B containing lipoproteins within the arterial subendothelial matrix (ECM) is an early event in atherosclerosis. When lipoprotein lipase, a constituent of the ECM, is prebound to ECM both LDL and oxidized LDL binding is greatly enhanced. In this study we compared the binding of lipoprotein(a) (Lp(a)), a lipoprotein correlated with atherosclerosis and restenosis, to ECM in the presence of varying concentrations of LPL. Without LPL, Lp(a) binding was low and non-saturable. In the presence of LPL, Lp(a) retention increased from 2.7 x 10(-7) to 1.13 x 10(-4) nmoles. Scatchard analysis demonstrated that the affinities of both Lp(a) and LDL to lipase were similar. In competition experiments, LDL, apoE, polymers of lysine and arginine were all capable of preventing the lipase specific [125I]Lp(a) retention. However, neither collagen nor fibronectin were capable of blocking or displacing [125I]Lp(a) from the lipase bound to ECM. In a separate set of experiments, when ECM was not saturated with lipase, both fibronectin and collagen (at 10-fold protein excess) prevented approximately 40% of total [125I]Lp(a) retention to ECM. These data suggest, in the absence of lipase, apo(a) may regulate the binding of Lp(a) to ECM. Whereas, lipase enhanced the binding of Lp(a) to ECM, most probably through the apoB moiety of the Lp(a) particle.
Atherosclerosis 1999 Jan
PMID:Lipoprotein lipase greatly enhances the retention of lipoprotein(a) to endothelial cell-matrix. 992 May 9

Low density lipoproteins (LDL) contain apolipoprotein B-100 and are cholesteryl ester-rich, triglyceride-poor macromolecules, arising from the lipolysis of very low density lipoproteins. This review will describe the receptors responsible for uptake of whole LDL particles (holoparticle uptake), and the selective uptake of LDL cholesteryl ester. The LDL-receptor mediates the internalization of whole LDL through an endosomal-lysosomal pathway, leading to complete degradation of LDL. Increasing LDL-receptor expression by pharmacological intervention efficiently reduces blood LDL concentrations. The lipolysis stimulated receptor and LDL-receptor related protein may also lead to complete degradation of LDL in presence of free fatty acids and apolipoprotein E- or lipase-LDL complexes, respectively. Selective uptake of LDL cholesteryl ester has been demonstrated in the liver, especially in rodents and humans. This activity brings five times more LDL cholesteryl ester than the LDL-receptor to human hepatoma cells, suggesting that it is a physiologically significant pathway. The lipoprotein binding site of HepG2 cells mediates this process and recognizes all lipoprotein classes. Scavenger receptor class B type I and CD36, which mediate the selective uptake of high density lipoprotein cholesteryl ester, are potentially involved in LDL cholesteryl ester selective uptake, since they both bind LDL with high affinity. It is not known whether they are identical to the uncloned lipoprotein binding site and if the selective uptake of LDL cholesteryl ester produces a less atherogenic particle. If this is verified, pharmacological up-regulation of LDL cholesteryl ester selective uptake may become another therapeutic approach for reducing blood LDL-cholesterol levels and the risk of atherosclerosis.
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PMID:Low density lipoprotein uptake: holoparticle and cholesteryl ester selective uptake. 1053 83


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