Plasma Lecithin:cholesterol Acyltransferase Research Articles

Lipid Lowering potential of Andrographis paniculata (Nees)

Aim: Atherosclerosis and associated complications is now the major cause of myocardial morbidity and mortality worldwide. Therefore we have selected the Andrographis paniculata for the development of lipid lowering drug. Material and Methods: The lipid lowering activity of mixture of andrographaloides isolated from the leaves of the Andrographis paniculata has been studied in Triton and cholesterol fed hyperlipidemic rats (in vivo). Results: Serum lipids were found to be lowered by andrographaloides (at 50 mg/kg.) in Triton WR-1339 induced hyperlipidemia in experimental animals. Chronic feeding of this mixture of andrographolides (at 25 mg/kg) in animals, simultaneously fed with high fat diet (HFD) for 30 days caused lowering in the lipid and apoprotein levels of very low density (VLDL) and low density lipoproteins (LDL) It has also increased high density lipoprotein (HDL). Andrographaloides activated lipolytic enzymes in plasma and liver lipids. The hypolipidemic activity of the andrographaloides mixture is mediated through increased faecal bile acid excretion and enhanced plasma lecithin-cholesterol acyl transferase activity. Conclusion: Mixture of Andrographolides was found to lower the lipids in experimental animals.

Alterations in plasma lecithin:cholesterol acyltransferase and myeloperoxidase in acute myocardial infarction: Implications for cardiac outcome

BackgroundThe cholesterol esterifying enzyme, lecithin:cholesterol acyltransferase (LCAT), plays a key role in HDL maturation and remodeling. Myeloperoxidase (MPO) may compromise LCAT enzymatic activity. We tested the extent to which plasma LCAT activity is altered in acute myocardial infarction (MI) in conjunction with abnormal MPO levels. We also assessed the impact of LCAT and MPO on newly developed major adverse cardiovascular events (MACE). MethodsTwo-hundred one consecutive patients referred for acute chest pain of whom 134 had MI (95 with ST-elevation) participated. Forty-five new MACE were ascertained during 1203 (range 13–1745) days of follow-up among 185 patients. Plasma LCAT activity was measured using an exogenous substrate assay. MPO mass was assayed by chemiluminescent microparticle immunoassay. ResultsPlasma LCAT activity was decreased by 15%, coinciding with 7-fold increased MPO levels in acute MI patients vs. patients with non-cardiac chest pain (p < 0.001 for both; correlation: r = −0.343, p < 0.001). MI at admission was associated independently with both lower plasma LCAT activity and higher MPO (age- and sex-adjusted odds ratio per 1 SD increment: 0.46 (95% CI, 0.31–0.68), p < 0.001 and 7.58 (95% CI, 3.34–17.11), p < 0.001, respectively). In an analysis with LCAT and MPO together these associations were modestly attenuated. MPO mass (hazard ratio: 1.59 (95% CI, 1.15–2.19), p = 0.004), but not LCAT activity (hazard ratio: 0.87 (95% CI, 0.65–1.19), p = 0.39), predicted newly manifest MACE. ConclusionIn acute MI patients, plasma LCAT activity is decreased coinciding with increased MPO levels. Higher MPO but not lower LCAT activity prospectively predicts adverse cardiac outcome.

Lipid-lowering effect of molluscan (Katelysia opima) glycosaminoglycan (GAG) in hypercholesterolemic induced rats

Identifying pharmacologically safe lipid-lowering 'deliverables' could potentiate therapeutic outcome for diet-induced atherogenesis. Accordingly, we investigated the potential of molluscan (Katelysia opima) glycosaminoglycan (GAG) in modulating the early lipid changes in atherogenesis. Wistar rats were fed a diet with (n=24) or without (n=6) hypercholesterolemic atherogenic CCT (rat chow supplemented with 4% cholesterol, 1% cholic acid, and 0.5% thiouracil) for 17 days. CCT-fed rates were (i) treated with isolated molluscan GAG (40 mg/kg/day, s.c.) for 10 days after the introduction of CCT diet, (ii) cotreated with GAG (40 mg/kg/day, s.c.) for 17 days, or (iii) treated with heparin (200 units/kg/day, s.c.) for 10 days after the introduction of CCT. The increases induced by CCT diet in the plasma levels of cholesterol, triglycerides, high-density lipoprotein, very-low-density lipoprotein, and low-density lipoprotein were completely attenuated with GAG treatment. Consistently, alterations induced by CCT diet in the levels of plasma lecithin cholesterol acyltransferase and lipoprotein lipase activities were restored to baseline levels with GAG treatment. Coherently, histology revealed a decrease associated with GAG treatment in the CCT-diet-induced foam cells (in aorta), tubular damages (kidney), and lipid accumulations (liver). Together, these results suggest that GAG may exert antiatherogenesis potential by significantly attenuating lipid modulations derived by a high-fat diet. Further, the data imply that the GAG extracts may comprehensively prevent hypercholesterolemia-associated tissue damage and could thus serve as a therapeutic deliverable for hypercholesterolemia.

Hybrid benzofuran–bisindole derivatives: New prototypes with promising anti-hyperlipidemic activities

A series of different benzofuran–bisindole hybrids were synthesized and evaluated in vitro for their antioxidant and in vivo for antidyslipidemic activity in triton WR-1339 induced hyperlipidemic rats. Among the series, compounds 4a, 4c, 4h and 4j showed significant decrease in plasma levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG) followed by increase in post heparin lipolytic activity (PHLA). In addition, the active hybrids possessed moderate antioxidant properties and increased the plasma lecithin cholesterol acyltransferase (LCAT) activity, which plays a key role in lipoprotein metabolism contributing to an increased level of HDL-C in serum. These results indicate that these hybrids constitute novel prototypes for the management of dyslipidemia.

A fluorescence method to detect and quantitate sterol esterification by lecithin:cholesterol acyltransferase

We describe a simple but sensitive fluorescence method to accurately detect the esterification activity of lecithin:cholesterol acyltransferase (LCAT). The new assay protocol employs a convenient mix, incubate, and measure scheme. This is possible by using the fluorescent sterol dehydroergosterol (DHE) in place of cholesterol as the LCAT substrate. The assay method is further enhanced by incorporation of an amphiphilic peptide in place of apolipoprotein A-I as the lipid emulsifier and LCAT activator. Specific fluorescence detection of DHE ester synthesis is achieved by employing cholesterol oxidase to selectively render unesterified DHE nonfluorescent. The assay accurately detects LCAT activity in buffer and in plasma that is depleted of apolipoprotein B lipoproteins by selective precipitation. Analysis of LCAT activity in plasmas from control subjects and sickle cell disease (SCD) patients confirms previous reports of reduced LCAT activity in SCD and demonstrates a strong correlation between plasma LCAT activity and LCAT content. The fluorescent assay combines the sensitivity of radiochemical assays with the simplicity of nonradiochemical assays to obtain accurate and robust measurement of LCAT esterification activity.

Skew of Plasma Low- and High-Density Lipoprotein Distributions to Less Dense Subfractions in Normotriglyceridemic Chronic Kidney Disease Patients on Maintenance Hemodialysis Treatment

Background: Plasma levels of small, dense low-density lipoprotein (LDL) were reported to increase in chronic kidney disease (CKD) patients on hemodialysis (HD), but most of these patients were hypertriglyceridemic. Plasma levels of small, dense LDL are known to increase in hypertriglyceridemic subjects. Therefore, to investigate the direct effect of CKD on the distribution of LDL subfractions, we investigated the distribution of LDL subfractions in normotriglyceridemic CKD patients on HD. Methods: The levels of plasma lipoprotein subfractions and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), which markedly influence the distributions of plasma LDL and high-density lipoprotein (HDL) subfractions, were compared between 40 HD patients and 40 normolipidemic controls. Plasma lipoproteins were subfractionated into seven subfractions by ultracentrifugation. Results: Plasma levels of cholesterol (C) in remnant-like particle, which is equivalent to the triglyceride (TG)-rich lipoprotein remnant, were twice as high in HD patients as those in controls with matched TG levels. Plasma levels of C and TG in VLDL and IDL (intermediate density lipoprotein) were slightly higher in HD patients than in controls. The C/TG ratio of VLDL was significantly higher in HD patients than in controls. In comparison with the corresponding values in controls, the C and TG levels in low-density LDL and HDL₂ in HD patients were high, whereas those in medium-density LDL, high-density LDL, and HDL₃ were low. Plasma LCAT activity and CETP mass were lower in HD patients than in controls. Conclusion: Distribution of LDL and HDL skewed toward less dense fractions in normotriglyceridemic CKD patients on HD. A decrease in reverse C transport likely played an important role in these changes in the patients.

The effect of HIV infection on atherosclerosis and lipoprotein metabolism: A one year prospective study

ObjectivesHIV infection is associated with dyslipidaemia and increased risk of cardiovascular disease. The effects of HIV infection and antiretroviral treatment on surrogate markers of atherosclerosis, and lipoprotein metabolism were evaluated in a 12 month prospective study. Methods and resultsTreatment-naive HIV patients were recruited into one of three groups: untreated HIV infection not likely to require initiation of antiretroviral therapy (ART) for at least 12 months; initiating treatment with non nucleoside reverse transcriptase inhibitor-containing ART regimen and initiating treatment with protease inhibitor-containing ART regimen. The patients underwent assessment of carotid intima-media thickness (cIMT), pulse wave velocity (PWV), brachial flow-mediated dilation (FMD) and variables of plasma lipoprotein metabolism at baseline and 12 months. The findings were compared with published values for age and sex matched HIV-negative healthy subjects in a cross-sectional fashion. cIMT and FMD were lower while PWV was higher in HIV-patients compared with HIV-negative individuals; none of the markers changed significantly during 12 months follow up. HIV patients had hypoalphalipoproteinemia and elevated plasma levels of lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein. The only significant changes in lipid-related variables were elevation of total cholesterol and triglycerides in patients treated with PI-containing regimen and elevation of plasma LCAT levels in patients treated with NNRTI-containing regimen. The ability of whole and apoB-depleted plasma to effect cholesterol efflux was not impaired in all three groups. ConclusionsThis study did not find evidence for rapid progression of subclinical atherosclerosis and deterioration of dyslipidaemia in HIV patients within 1 year.

Lipid Oxidation in Carriers of Lecithin:Cholesterol Acyltransferase Gene Mutations

Lecithin:cholesterol acyltransferase (LCAT) has been shown to play a role in the depletion of lipid oxidation products, but this has so far not been studied in humans. In this study, we investigated processes and parameters relevant to lipid oxidation in carriers of functional LCAT mutations. In 4 carriers of 2 mutant LCAT alleles, 63 heterozygotes, and 63 family controls, we measured activities of LCAT, paraoxonase 1, and platelet-activating factor-acetylhydrolase; levels of lysophosphatidylcholine molecular species, arachidonic and linoleic acids, and their oxidized derivatives; immunodetectable oxidized phospholipids on apolipoprotein (apo) B-containing and apo(a)-containing lipoproteins; IgM and IgG autoantibodies to malondialdehyde-low-density lipoprotein and IgG and IgM apoB-immune complexes; and the antioxidant capacity of high-density lipoprotein (HDL). In individuals with LCAT mutations, plasma LCAT activity, HDL cholesterol, apoA-I, arachidonic acid, and its oxidized derivatives, oxidized phospholipids on apo(a)-containing lipoproteins, HDL-associated platelet-activating factor-acetylhydrolase activity, and the antioxidative capacity of HDL were gene-dose-dependently decreased. Oxidized phospholipids on apoB-containing lipoproteins was increased in heterozygotes (17%; P<0.001) but not in carriers of 2 defective LCAT alleles. Carriers of LCAT mutations present with significant reductions in LCAT activity, HDL cholesterol, apoA-I, platelet-activating factor-acetylhydrolase activity, and antioxidative potential of HDL, but this is not associated with parameters of increased lipid peroxidation; we did not observe significant changes in the oxidation products of arachidonic acid and linoleic acid, immunoreactive oxidized phospholipids on apo(a)-containing lipoproteins, and IgM and IgG autoantibodies against malondialdehyde-low-density lipoprotein. These data indicate that plasma LCAT activity, HDL-associated platelet-activating factor-acetylhydrolase activity, and HDL cholesterol may not influence the levels of plasma lipid oxidation products.

Steroidal saponin from Chlorophytum nimonii (Grah) with lipid-lowering and antioxidant activity

Aim: Since drugs used these days to lower the lipids are all synthetic drugs, they have some or the other side effects, therefore in search of cheaper lipid-lowering drugs with no side effects, we have conducted a study on Chlorophytum nimonii for its lipid-lowering and antioxidant properties. Materials and Methods: Chloragin and Gemfibrozil both caused a significant decrease in the serum level of lipids in triton-induced hyperlipidemic rats, and this model has been successfully used for the evaluation of lipid-lowering activity of chloragin in the rats. Results and Discussion: The lipid-lowering action of steroidal saponin and chloragin of the C. nimonii has been studied in triton model (in cholesterol-fed hyperlipidemic rats) in vivo and antioxidant activity in vitro model. Serum lipids were found to be lowered by the steroidal saponin (100 mg/kg body weight) in triton WR-1339-induced hyperlipidemia. Chronic feeding of this compound (50 mg/kg) in animals simultaneously fed with high-fat diet for 30 days caused lowering in the lipid and lipoproteins levels of low-density lipoproteins in experimental animals. Conclusion: Chloragin activates lipolytic enzymes in plasma and liver. Chloragin is mediated through inhibition of hepatic lipids, increased fecal bile acid excretion, and enhanced plasma lecithin cholesterol acyl transferase activities. Chloragin from the C. nimonii showed potent antioxidant activity as well.

The thienotriazolodiazepine Ro 11-1464 increases plasma apoA-I and promotes reverse cholesterol transport in human apoA-I transgenic mice

Ro 11-1464 is a thienotriazolodiazepine previously described to selectively stimulate apolipoprotein A-I (apoA-I) production and mRNA level in human liver cells. Here, we studied its effects upon oral administration to human apoA-I transgenic (hapoA-I) mice. HapoA-I mice were treated for 5 days with increasing doses of Ro 11-1464. Macrophage reverse cholesterol transport (mph-RCT) was assessed by following [(3) H]-cholesterol mobilization from pre-labelled i.p. injected J774 macrophages to plasma, liver and faeces. Effects on plasma lipids, apoproteins, lecithin-cholesterol : acyltransferase (LCAT) and liver enzymes, as well as on faecal excretion of cholesterol and bile salts, and on liver lipids and mRNA contents were determined. Treatment with Ro 11-1464 300 mg·kg(-1) ·day(-1) resulted in a nearly 2-fold increase in plasma apoA-I, a 2- to 3-fold increase in the level of large sized-pre-β high-density lipoprotein and a 3-fold selective up-regulation of hepatic apoA-I mRNA, but a marked decrease in all plasma lipids and LCAT activity. Mpm-RCT was decreased in blood but markedly increased in faecal sterols (4-fold) and bile acids (1.7-fold). However, liver weight and liver enzymes in plasma were also increased, in parallel with an increase in liver cholesterol ester content (all these effect being significant). In this model Ro 11-1464 causes increased hepatic expression and plasma levels of apoA-I and a suppression of LCAT, and a marked enhancement of reverse cholesterol transport, but also some symptoms of liver toxicity. The compound may therefore be a prototype for a next generation of anti-atherosclerotic medicines.

Small molecule activation of lecithin cholesterol acyltransferase modulates lipoprotein metabolism in mice and hamsters

The objective was to assess whether pharmacological activation of lecithin cholesterol acyltransferase (LCAT) could exert beneficial effects on lipoprotein metabolism. A putative small molecule activator (compound A) was used as a tool compound in in vitro and in vivo studies. Compound A increased LCAT activity in vitro in plasma from mouse, hamster, rhesus monkey, and human. To assess the acute pharmacodynamic effects of compound A, C57Bl/6 mice and hamsters received a single dose (20 mg/kg) of compound A. Both species displayed a significant increase in high-density lipoprotein cholesterol (HDLc) and a significant decrease in non-HDLc and triglycerides acutely after dosing; these changes tracked with ex vivo plasma LCAT activity. To examine compound A's chronic effect on lipoprotein metabolism, hamsters received a daily dosing of vehicle or of 20 or 60 mg/kg of compound A for 2 weeks. At study termination, compound treatment resulted in a significant increase in HDLc, HDL particle size, plasma apolipoprotein A-I level, and plasma cholesteryl ester (CE) to free cholesterol ratio, and a significant reduction in very low-density lipoprotein cholesterol. The increase in plasma CE mirrored the increase in HDL CE. Triglycerides trended toward a dose-dependent decrease in very low-density lipoprotein and HDL, with multiple triglyceride species reaching statistical significance. Gallbladder bile acids content displayed a significant and more than 2-fold increase with the 60 mg/kg treatment. We characterized pharmacological activation of LCAT by a small molecule extensively for the first time, and our findings support the potential of this approach in treating dyslipidemia and atherosclerosis; our analyses also provide mechanistic insight on LCAT's role in lipoprotein metabolism.

AAV8-Mediated Long-Term Expression of Human LCAT Significantly Improves Lipid Profiles in hCETP;Ldlr+/− Mice

Lecithin:cholesterol acyltransferase (LCAT) is the key circulating enzyme responsible for high-density lipoprotein (HDL) cholesterol esterification, HDL maturation, and potentially reverse cholesterol transport. To further explore LCAT's mechanism of action on lipoprotein metabolism, we employed adeno-associated viral vector (AAV) serotype 8 to achieve long-term (32-week) high level expression of human LCAT in hCETP;Ldlr(+/-) mice, and characterized the lipid profiles in detail. The mice had a marked increase in HDL cholesterol, HDL particle size, and significant reduction in low-density lipoprotein (LDL) cholesterol, plasma triglycerides, and plasma apoB. Plasma LCAT activity significantly increased with humanized substrate specificity. HDL cholesteryl esters increased in a fashion that fits human LCAT specificity. HDL phosphatidylcholines trended toward decrease, with no change observed for HDL lysophosphatidylcholines. Triglycerides reduction appeared to reside in all lipoprotein particles (very low-density lipoprotein (VLDL), LDL, and HDL), with HDL triglycerides composition highly reflective of VLDL, suggesting that changes in HDL triglycerides were primarily driven by the altered triglycerides metabolism in VLDL. In summary, in this human-like model for lipoprotein metabolism, AAV8-mediated overexpression of human LCAT resulted in profound changes in plasma lipid profiles. Detailed lipid analyses in the lipoprotein particles suggest that LCAT's beneficial effect on lipid metabolism includes not only enhanced HDL cholesterol esterification but also improved metabolism of apoB-containing particles and triglycerides. Our findings thus shed new light on LCAT's mechanism of action and lend support to its therapeutic potential in treating dyslipidemia.

Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. LCAT is a major factor in HDL remodeling and metabolism, and it has long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). The effect of LCAT on human atherogenesis is still controversial. In the present study, the plasma LCAT concentration was measured in all subjects (n = 540) not on drug treatment at the time of enrollment in the multicenter, longitudinal, observational IMPROVE study. Mean and maximum intima-media thickness (IMT) of the whole carotid tree was measured by B-mode ultrasonography in all subjects. In the entire cohort, LCAT quartiles were not associated with carotid mean and maximum IMT (P for trend 0.95 and 0.18, respectively), also after adjustment for age, gender, HDL-cholesterol (HDL-C), and triglycerides. No association between carotid IMT and LCAT quartiles was observed in men (P=0.30 and P=0.99 for mean and maximum IMT, respectively), whereas carotid IMT increased with LCAT quartiles in women (P for trend 0.14 and 0.019 for mean and maximum IMT, respectively). The present findings support the concept that LCAT is not required for an efficient reverse cholesterol transport and that a low plasma LCAT concentration and activity is not associated with increased atherosclerosis.

Hepatic Deficiency of Low Density Lipoprotein Receptor-related Protein-1 Reduces High Density Lipoprotein Secretion and Plasma Levels in Mice

The low density lipoprotein receptor-related protein-1 (LRP1) is known to serve as a chylomicron remnant receptor in the liver responsible for the binding and plasma clearance of apolipoprotein E-containing lipoproteins. Previous in vitro studies have provided evidence to suggest that LRP1 expression may also influence high density lipoprotein (HDL) metabolism. The current study showed that liver-specific LRP1 knock-out (hLrp1(-/-)) mice displayed lower fasting plasma HDL cholesterol levels when compared with hLrp1(+/+) mice. Lecithin:cholesterol acyl transferase and hepatic lipase activities in plasma of hLrp1(-/-) mice were comparable with those observed in hLrp1(+/+) mice, indicating that hepatic LRP1 inactivation does not influence plasma HDL remodeling. Plasma clearance of HDL particles and HDL-associated cholesteryl esters was also similar between hLrp1(+/+) and hLrp1(-/-) mice. In contrast, HDL secretion from primary hepatocytes isolated from hLrp1(-/-) mice was significantly reduced when compared with that observed with hLrp1(+/+) hepatocytes. Biotinylation of cell surface proteins revealed decreased surface localization of the ATP-binding cassette, subfamily A, member 1 (ABCA1) protein, but total cellular ABCA1 level was not changed in hLrp1(-/-) hepatocytes. Finally, hLrp1(-/-) hepatocytes displayed reduced binding capacity for extracellular cathepsin D, resulting in lower intracellular cathepsin D content and impairment of prosaposin activation, a process that is required for membrane translocation of ABCA1 to facilitate cholesterol efflux and HDL secretion. Taken together, these results documented that hepatic LRP1 participates in cellular activation of lysosomal enzymes and through this mechanism, indirectly modulates the production and plasma levels of HDL.

Oxidized Low-Density Lipoprotein Is Negatively Correlated With Lecithin-Cholesterol Acyltransferase Activity in Type 2 Diabetes Mellitus

IntroductionIt is now believed that the oxidative modification of plasma lipoproteins enhance their atherogenicity in patients with type 2 diabetes. Because a variety of highly reactive lipid peroxidation products can transfer from oxidized low-density lipoprotein (ox-LDL) to high-density lipoprotein -cholesterol, the authors evaluated the association between ox-LDL and lecithin-cholesterol acyl-transferase (LCAT) activity, a key enzyme in reverse cholesterol transport and HDL remodeling. MethodsA total of 45 patients with diabetes and 45 age-, sex- and body mass index-matched healthy adult volunteers were enrolled. Fasting blood samples were obtained, and plasma glucose, lipid profile, creatinine, insulin, ox-LDL and LCAT activity were measured. Homeostasis model assessment of insulin resistance was also calculated. ResultsPatients with diabetes, compared with healthy participants, had a significantly higher ox-LDL (17.16 ± 3.75 U/L versus 7.93 ± 1.92 U/L, P < 0.001) and lower LCAT activity (73.7 ± 9.1 μmol/L/hr versus 88.7 ± 4.5 μmol/L/hr, P < 0.001). The higher level of LCAT activity completely disappeared after adjustment for ox-LDL. LCAT activity had a significant (P < 0.001) inverse correlation with ox-LDL (r = -0.77) in patients with diabetes and healthy participants (r =-0.75). ConclusionLCAT activity is significantly decreased in type 2 diabetes. The lower LCAT activity in type 2 diabetes might be through ox-LDL mechanism. ox-LDL may adversely affect high-density lipoprotein -cholesterol metabolism by reducing LCAT activity.

Simvastatin reduces atherogenesis and promotes the expression of hepatic genes associated with reverse cholesterol transport in apoE-knockout mice fed high-fat diet

BackgroundStatins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet.ResultsThe atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/- mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups.ConclusionsWe demonstrated the anti-atherogenesis effects of simvastatin in apoE-/- mice fed a high-fat diet. We confirmed here for the first time simvastatin increased the expression of hepatic ABCB4 and ABCG5, which involved in secretion of cholesterol and bile acids into the bile, besides upregulated ABCA1 and apoA-I. The elevated HDL-C level, increased LCAT activity and the stimulation of several transporters involved in RCT may all contribute to the anti-atherosclerotic effect of simvastatin.

NO levels in diabetes mellitus: Effects of l-NAME and insulin on LCAT, Na+/K+ ATPase activity and lipid profile

ObjectivesDiabetes mellitus (DM) is a chronic disease and one of the most important health problems. Several factors may be responsible for the complications of diabetes mellitus including alterations in the activities of sodium–potassium adenosine triphosphatase (Na+/K+ ATPase) and lecithin:cholesterol acyltransferase (LCAT) and also levels of nitric oxide (NO). We have investigated the effects of alterations in serum NO levels on activities of erythrocyte membran Na/K ATPase and serum LCAT enzymes. Materials and methodsThe experiments were performed on male rats divided into four groups: group 1, control (standart diet); group 2, diabetic control (single dose of 65mg/kg of streptozotocin (STZ), i.p); group 3, STZ+insulin (8IU/kg/day s.c.); group 4 (STZ+l-NAME 5mg/kg/day orally). ResultStreptozotocin-induced diabetic rats, showed a significant increase in blood glucose and serum cholesterol (C) and triglyceride (TG). Compared to the control group with diabetic group plasma LCAT concentrations and erythrocyte membrane Na+/K+ ATPase were found to be decreased. Activities of Na+/K+ ATPase and serum NO level were decreased with the administration of l-NAME. We observed that insulin was ameliorated in all parameters. ConclusionsSerum NO levels is related to erythrocyte membrane Na+/K+ ATPase activity. But serum NO levels did not affect the plasma LCAT activity and serum lipid profiles.

Protective effect of rutin on lipids, lipoproteins, lipid metabolizing enzymes and glycoproteins in streptozotocin-induced diabetic rats

The protective role of rutin on lipids, lipoproteins, lipid metabolizing enzymes and glycoproteins in streptozotocin-induced diabetic rats has been studied. A single intraperitoneal injection of streptozotocin (50 mg kg(-1)) to rats led to a significant (P < 0.05) increase in the levels of lipids (cholesterol, triglycerides, free fatty acids and phospholipids) in plasma and tissues (liver, kidney, heart and brain). The levels of low density and very low density lipoprotein (LDL and VLDL, respectively) cholesterol were increased, whereas the levels of high density lipoprotein (HDL) cholesterol were decreased significantly (P < 0.05) in plasma. The activity of 3-hydroxy 3-methylglutaryl coenzyme A (HMG CoA) reductase increased significantly (P < 0.05) in liver, kidney and heart, and the activity of lipoprotein lipase (LPL) and lecithin cholesterol acyltransferase (LCAT) decreased significantly (P < 0.05) in the plasma of diabetic rats. Streptozotocin injection also increased the levels of glycoproteins such as hexose, hexosamine, fucose and sialic acid in plasma, liver and kidney. Oral administration of rutin to streptozotocin-induced diabetic rats significantly (P < 0.05) decreased the levels of lipids in plasma and tissues. The levels of plasma HDL-cholesterol increased and the levels of LDL- and VLDL-cholesterol decreased significantly (P < 0.05). The activity of HMG CoA reductase decreased in the tissues and the activity of plasma LPL and LCAT increased significantly (P < 0.05). The levels of glycoproteins were found to be significantly (P < 0.05) decreased in plasma, liver and kidney of rutin-treated diabetic rats. Rutin administration to normal rats did not exhibit any significant (P < 0.05) changes in any of the parameters studied. In conclusion, the beneficial effect of rutin on lipids, lipoproteins, lipid metabolizing enzymes and glycoproteins could be due to its antioxidant property.

Plasma lecithin:cholesterol acyltransferase activity modifies the inverse relationship of C-reactive protein with HDL cholesterol in nondiabetic men

Lecithin:cholesterol acyltransferase (LCAT) is instrumental in high-density lipoprotein (HDL) maturation, but high LCAT levels do not predict low cardiovascular risk. LCAT may affect antioxidative or anti-inflammatory properties of HDL. We determined the relationship of plasma high-sensitivity C-reactive protein (CRP) with LCAT activity and evaluated whether LCAT activity modifies the decreasing effect of HDL cholesterol (HDL-C) on CRP, as an estimate of its anti-inflammatory properties. Plasma HDL-C, apolipoprotein (apo) A-I and LCAT activity (exogenous substrate method) were measured in 260 nondiabetic men without cardiovascular disease. CRP was correlated inversely with HDL-C and apo A-I, and positively with LCAT activity ( P < 0.01 to 0.001). Multivariate regression analysis demonstrated that age- and smoking-adjusted plasma CRP levels were associated negatively with HDL-C ( β = − 0.224, P < 0.001) and positively with LCAT activity ( β = 0.119, P = 0.034), as well as with the interaction between HDL-C and LCAT activity ( β = 0.123, P = 0.026). There was also an interaction between apo A-I and LCAT activity on CRP ( β = 0.159, P = 0.005). These relationships remained similar after adjustment for apo B-containing lipoproteins. In conclusion, the inverse relationship of HDL-C with CRP is attenuated by LCAT activity at higher HDL-C levels. It is hypothesized that LCAT could mitigate HDL's anti-inflammatory or antioxidative properties at higher HDL-C concentrations.

High plasma lecithin:cholesterol acyltransferase activity does not predict low incidence of cardiovascular events: Possible attenuation of cardioprotection associated with high HDL cholesterol

The cholesterol esterifying enzyme, lecithin:cholesterol acyltransferase (LCAT), is crucial in high density lipoprotein (HDL) metabolism. The role of LCAT activity on incident cardiovascular disease (CVD) is unknown. We determined the association of incident CVD with plasma LCAT activity, and evaluated whether LCAT may modify the cardioprotective effect of higher HDL cholesterol. In a community-based prospective nested case-control study (PREVEND cohort), an exogenous substrate assay was used to measure plasma LCAT activity in 116 men who developed CVD (cases) and in 111 male controls. Plasma LCAT activity was 5% higher in cases (P=0.027) in association with higher total cholesterol, non-HDL cholesterol and triglycerides. Age-adjusted incident CVD was increased with higher LCAT activity (continuous variable: hazard ratio (HR) 1.23; 95% CI 1.01–1.49, P=0.037; upper quartile vs. lowest 3 quartiles: HR 1.60; 95% CI 1.07–2.39, P=0.021). This relationship was not significant after adjustment for lipids. Compared to subjects with HDL cholesterol above the median and lower LCAT activity (lowest 3 quartiles) the age-adjusted cardiovascular risk was elevated in subjects with similarly higher HDL cholesterol and higher LCAT activity (HR 2.38; 95% CI 1.27–4.49, P=0.007), lower HDL cholesterol and lower LCAT activity (HR 2.58; 95% CI 1.64–4.49, P<0.001) and lower HDL cholesterol and higher LCAT activity (HR 2.76; 95% CI 1.58–4.83, P<0.001). These HRs were unchanged after non-HDL cholesterol and triglyceride adjustment. In conclusion, high plasma LCAT activity does not predict reduced CVD risk, and may attenuate cardioprotection associated with higher HDL cholesterol.