Remnant-like Particle Research Articles

ドック受診者におけるRemnant Like Particles(RLP)の検討(第二報) ―耐糖能異常(IGT)及び脂肪肝について―

ドック受診者におけるRemnant Like Particles(RLP)の検討(第二報) ―耐糖能異常(IGT)及び脂肪肝について―

レムナント様リボ蛋白(RLP)コレステロールとインスリン抵抗性との関連

レムナント様リボ蛋白(RLP)コレステロールとインスリン抵抗性との関連

Post‐prandial remnant lipoprotein metabolism in autosomal recessive hypercholesterolaemia

Phenotype of autosomal recessive hypercholesterolaemia (ARH), a rare lipid disorder, is known to be milder than that of homozygous familial hypercholesterolaemia (FH) with LDL receptor gene mutation. However, few data exist regarding the functional differences in ARH and FH particularly in terms of remnant-like particles' (RLP) metabolism. Blood sampling was performed up to 6h after OFTT cream loading (50 g/body surface area) with 2-h intervals in a single ARH proband, four heterozygous FH patients with LDL receptor gene mutation and four normal controls. Plasma lipoprotein and RLP fraction were determined by HPLC system. The area under curve (AUC) of each lipoprotein including RLP fractions was evaluated. The AUC of TG, RLP cholesterol (RLP-C) and RLP triglyceride (RLP-TG) levels of heterozygous FH subjects was significantly higher than those of controls (466±71 mg/dL×h vs. 303±111 mg/dL×h, P<0·05; 35±7 mg/dL×h vs. 21±8 mg/dL×h, P<0·05; 124±57 mg/dL×h vs. 51±13 mg/dL×h, P<0·05, respectively). Under these conditions, those values of ARH were close to those of controls (310 mg/dL×h, 22 mg/dL×h, 23 mg/dL×h, respectively). These data demonstrate that unlike in FH, RLP clearance is preserved in ARH. The preservation of post-prandial RLP clearance may contribute to the mild phenotype of ARH compared with FH.

A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy

It remains undetermined whether the addition of ezetimibe to ongoing statin therapy is more effective than increasing the dose of statin for reducing remnant lipoprotein levels in patients with remnant lipoproteinemia on previous statin treatment. This study examined whether combined ezetimibe and statin therapy resulted in a greater improvement in remnant lipoprotein levels and endothelial function than with the dose of statin in patients with remnant lipoproteinemia on previous statin treatment. A total of 63 patients with stable coronary artery disease and high levels of remnant-like lipoprotein particle cholesterol (RLP-C) (≥5.0 mg/dL) on statin treatment were assigned randomly to two groups and treated with either addition of ezetimibe (10mg/day, n=32) or doubling of statin dose (n=31). The lipid profiles and flow-mediated dilation (FMD) of the brachial artery were measured at enrollment and after 6 months of treatment. Statin and ezetimibe combined therapy reduced RLP-C and improved FMD to a greater extent than doubling the statin dose (% reduction in RLP-C, 48 ± 18% vs. 33 ± 24%, respectively, p=0.01; % improvement in FMD, 47 ± 48% vs. 24 ± 23%, respectively, p=0.02). The addition of ezetimibe to ongoing statin treatment reduced RLP-C levels and improved endothelial dysfunction to a greater extent than doubling the statin dose in patients with high RLP-C levels on previous statin treatment. The present results are preliminary and should be confirmed by further studies on a larger number of study patients.

Triglyceride-rich lipoproteins in chronic kidney disease patients undergoing maintenance haemodialysis treatment

Plasma triglyceride (TG) levels were reported to be high in chronic kidney disease (CKD) patients undergoing haemodialysis (HD) treatment. One of the atherogenic causes of hypertriglyceridemia is the increase in TG-rich lipoprotein remnants, which are equivalent to remnant-like particle cholesterol (RLP-C). Here, we compared the plasma levels of TG, a representative indicator of TG-rich lipoproteins and RLP-C, as well as the TG/RLP-C ratio between CKD patients undergoing HD and controls, in an effort to elucidate the atherogenicity of TG-rich lipoproteins in CKD patients on HD. Plasma lipid and apo(lipo)protein levels and the TG/RLP-C ratio were compared between 49 CKD patients undergoing HD and 627 controls. Blood sampling for lipid and apoprotein analysis was performed in a 12-h fasting state. Controls were divided into four subgroups according to TG level (from highest to lowest). RLP-C and apo(lipo)proteins were measured using the immunoprecipitation method and turbidimetric immunoassay, respectively. In addition, a comparison between HD patients and age-, gender-, and plasma TG level-matched controls was performed. Plasma TG levels were 107 ± 70 (mean ± SD) mg/dl in HD patients and 115 ± 72 mg/dl in controls. Plasma RLP-C levels were 6.7 ± 4.5 mg/dl in HD patients and 4.6 ± 3.5 mg/dl in the controls (p < 0.0001). RLP-C levels decreased in descending order from the highest to the lowest TG group in controls. RLP-C levels were higher in HD patients than in controls with plasma TG levels of < 150 mg/dl (p < 0.0001). TG/RLP-C ratios were 19.0 ± 12.0 in HD patients and 25.9 ± 9.5 in controls (p < 0.0001). This ratio was significantly lower in HD patients than in all four TG subgroups. The comparison between HD patients and age-, gender-, plasma TG-matched controls revealed identical results. Plasma RLP-C levels were high, and the TG/RLP-C ratio was low in CKD patients undergoing HD treatment. These findings indicate that total plasma TG-rich lipoprotein levels were not increased, but the distribution of plasma TG-rich lipoproteins were skewed towards remnant fractions in CKD patients undergoing HD treatment; these plasma TG-rich lipoproteins appear to be more atherogenic than those in controls.

Similarities and differences between the effects of EPA and DHA on markers of atherosclerosis in human subjects

We have reviewed effects of long chain (LC) n-3 PUFA on markers of atherosclerosis in human subjects with a focus on individual effects of EPA and DHA. Initial results from epidemiological studies suggested that LC n-3 PUFA from fish oils (FO) reduced incidence of CVD; those results have been confirmed in interventional studies. Dietary intervention with n-3 PUFA decreased fasting and postprandial TAG, number of remnant-like chylomicron particles, large VLDL, and total and small dense LDL particles. It increased mean size of LDL particles by increasing number of large and decreasing those of small dense particles. With some exceptions, n-3 PUFA decreased blood pressure (BP) and heart rate (HR), flow-mediated dilation (FMD) and plasma concentrations of inflammatory markers. n-3 PUFA also decreased circulating adhesion molecules and intima-media thickness (IMT) in some but not other studies. For IMT, results varied with the sex and artery being examined. EPA effects on FMD are endothelial cell dependent, while those of DHA seem to be endothelial cell independent. Individually, both EPA and DHA decreased TAG and inflammatory markers, but only DHA decreased HR, BP and number of small dense LDL particles. Results varied because of dose and duration of n-3 PUFA, EPA:DHA, health status of subjects and other reasons. Future studies are needed to determine optimal doses of EPA and DHA individually, their synergistic, additive or antagonistic effects, and to understand underlying mechanisms. In conclusion, n-3 PUFA decreased several risk factors for atherosclerosis without any serious adverse effects.

Apolipoprotein B-48 as a determinant of endothelial function in obese subjects with type 2 diabetes mellitus: Effect of fenofibrate treatment

ObjectiveElevated triglyceride-rich lipoproteins may contribute to endothelial dysfunction in obese diabetic subjects. We investigated the association between plasma concentrations of chylomicron-related particles and endothelial function, and the corresponding responses to fenofibrate treatment. MethodsPlasma apolipoprotein (apo) B-48 and remnant-like particle (RLP)-cholesterol concentrations were measured in 28 obese subjects with T2DM. Flow-mediated endothelium-dependent dilation (FMD) and glyceryl-trinitrate mediated dilatation (GTNMD) in the brachial artery during reactive hyperaemia were examined by high-resolution ultrasound technique. ResultsIn univariate analysis, plasma apoB-48 and RLP-cholesterol concentrations were inversely associated with brachial artery FMD (r=−0.425 and −0.423, respectively, P<0.05), but not with GTNMD. In regression models including BMI and HOMA score, plasma apoB-48 was an independent predictors (P<0.05) of brachial artery FMD (β coefficient=−0.384). Replacing HOMA-IR score with plasma triglyceride, adiponectin or CRP concentrations did not alter the findings. The subjects were then randomized to a 12-week treatment period of either 200mg micronized fenofibrate or matching placebo. Compared with the placebo group, fenofibrate treatment (200mg daily for 12weeks) achieved significant increase in FMD (+34%) and reduction in plasma triglyceride (−42%), apoB-48 (−52%) and RLP-cholesterol (−51%) concentrations. The increase in FMD with fenofibrate was significantly associated with the corresponding decrease in plasma apoB-48 (r=−0.644, P<0.02) concentrations. ConclusionsOur findings demonstrate an association between changes in lipid metabolism and improvement in endothelial function in patients with diabetic dyslipidaemia treated with fenofibrate that may involve the effect of apoB-48 on endothelium-dependent vasodilator function.

Eicosapentaenoic Acid Supplementation Changes Fatty Acid Composition and Corrects Endothelial Dysfunction in Hyperlipidemic Patients

We investigated the effects of purified eicosapentaenoic acid (EPA) on vascular endothelial function and free fatty acid composition in Japanese hyperlipidemic subjects. In subjects with hyperlipidemia (total cholesterol ≥220 mg/dL and/or triglycerides ≥150 mg/dL), lipid profile and forearm blood flow (FBF) during reactive hyperemia were determined before and 3 months after supplementation with 1800 mg/day EPA. Peak FBF during reactive hyperemia was lower in the hyperlipidemic group than the normolipidemic group. EPA supplementation did not change serum levels of total, HDL, or LDL cholesterol, apolipoproteins, remnant-like particle (RLP) cholesterol, RLP triglycerides, or malondialdehyde-modified LDL cholesterol. EPA supplementation did not change total free fatty acid levels in serum, but changed the fatty acid composition, with increased EPA and decreased linoleic acid, γ-linolenic acid, and dihomo-γ-linolenic acid. EPA supplementation recovered peak FBF after 3 months. Peak FBF recovery was correlated positively with EPA and EPA/arachidonic acid levels and correlated inversely with dihomo-γ-linolenic acid. EPA supplementation restores endothelium-dependent vasodilatation in hyperlipidemic patients despite having no effect on serum cholesterol and triglyceride patterns. These results suggest that EPA supplementation may improve vascular function at least partly via changes in fatty acid composition.

Double-Blind Randomized Clinical Trial of the Effects of Ezetimibe on Postprandial Hyperlipidaemia and Hyperglycaemia

Ezetimibe selectively blocks intestinal cholesterol absorption by inhibiting Niemann-Pick C1-like 1 (NPC1L1) and reducing LDL cholesterol (LDL-C). In animals, ezetimibe reversed diet-induced obesity, liver steatosis, and insulin resistance. In humans, its potential effects on liver steatosis and insulin resistance have been suggested. We investigated the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia in obese subjects with dyslipidaemia in a double-blind randomized crossover trial. Twenty obese men with hypertriglyceridaemia were assigned randomly to an ezetimibe- or a placebo-precedence-treated group. Subjects in the ezetimibe group were treated with ezetimibe (10 mg/day) for the first 4 weeks, followed by a 4-week interval and then treated with placebo for another 4 weeks. The placebo group received these treatments in reverse order. Subjects were requested to fast for at least 12 hours and then received a standard meal. Blood samples were collected at 0, 30, 60, 120, 240, 360 and 480 minutes after the meal on Days 0, 28, 56 and 84 and were used to measure the lipid and glucose metabolism markers. Ezetimibe significantly decreased the postprandial serum triglyceride excursion (p=0.01) and fasting serum LDL-C, remnant-like particles(RLP) and ApoB48 levels (p<0.05). Postprandial glucose excursion, serum insulin levels, serum glucose-dependent insulinotropic polypeptide (GIP) and active glucagon-like peptide-1 (GLP-1) were not significantly affected by ezetimibe treatment. Ezetimibe restored the postprandial dysregulation of lipid but did not affect glucose metabolism in a double-blind randomized crossover trial.

Effects of Pitavastatin on Remnant-Like Lipoprotein Particle Cholesterol in Patients with Dyslipidemia: A Randomized Controlled Trial

Effects of Pitavastatin on Remnant-Like Lipoprotein Particle Cholesterol in Patients with Dyslipidemia: A Randomized Controlled Trial

Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Ezetimibe reduces serum low-density lipoprotein cholesterol (LDL-C) levels by inhibiting intestinal cholesterol absorption; however, the effects of ezetimibe, including its pleiotropic effects, have not been fully clarified. The aims of our study were to examine the efficacy of ezetimibe for hypercholesterolemia and its pleiotropic effects. Outpatients with hyper LDL-C levels were treated with 10 mg ezetimibe once a day for 12 weeks. Serum lipid profiles, atherosclerotic and inflammatory markers, glucose, insulin, liver function, and cholesterol absorption and synthesis markers were measured before and after treatment. Seventy-five patients treated with ezetimibe monotherapy and 16 patients treated with combined therapy of ezetimibe with different statins completed this study. Following 12 weeks of ezetimibe monotherapy, serum LDL-C, triglyceride, remnant-like particles cholesterol, matrix metalloproteinase-9, insulin, homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein, the relative mobility of the peak of the LDL fraction, and cholesterol absorption markers were significantly decreased, and high-density lipoprotein cholesterol and lathosterol were significantly increased. In the combined therapy group, LDL-C and cholesterol absorption markers were significantly decreased after treatment. In patients with a high basal ALT level that were treated with monotherapy, ALT and the AST/ALT ratio were significantly decreased and increased, respectively, after treatment. Ezetimibe ameliorated not only atherogenic lipid profiles but also atherosclerotic and inflammatory markers, insulin sensitivity, and liver dysfunction in Japanese hypercholesterolemia patients, suggesting that ezetimibe treatment is a beneficial and effective strategy for the treatment of hypercholesterolemia, especially patients with obesity, metabolic syndrome, and/or fatty liver.

Ezetimibe Improves Endothelial Function and Inhibits Rho-Kinase Activity Associated With Inhibition of Cholesterol Absorption in Humans

Ezetimibe is an inhibitor of cholesterol absorption in the intestine. We examined whether ezetimibe improves endothelial function, and if so, what mechanisms are involved. Nineteen healthy subjects (male/female 14/5; mean age, 31±3 [SD] years-old) were randomized to receive ezetimibe (10mg/day) or pravastatin (10mg/day) for 4 weeks in a cross-over manner with a 4-week washout interval. Lipid profiles, flow-mediated dilatation (FMD) and Rho-kinase activity of circulating leukocytes (the extent of phosphorylation of myosin binding subunit, a Rho-kinase substrate) were examined. We also evaluated remnant-like particle cholesterol (RLP-C) known as an up-regulator of Rho-kinase and cholesterol absorption status by measuring cholestanol and campesterol/lathosterol ratio (CLR) (both absorption markers). Although ezetimibe and pravastatin equally reduced low-density lipoprotein cholesterol (E: -25% vs. P: -21%), the CLR was reduced by ezetimibe but was rather increased by pravastatin (E: -41% vs. P: +37%; P<0.01). Reduction in RLP-C by ezetimibe was greater compared with pravastatin (E: -33% vs. P: -14%; P<0.05). Importantly, ezetimibe significantly improved FMD (26%, P<0.05) and reduced Rho-kinase activity (-21%, P<0.05), whereas pravastatin had no such effects. A significant correlation was noted between the reduction in cholestanol and the improvement in FMD (P<0.05). These results indicate that ezetimibe improves endothelial function and inhibits Rho-kinase activity associated with the inhibition of cholesterol absorption, suggesting novel anti-atherogenic effects of the agent in humans.

Novel Aspects of Nonfasting Lipemia in relation to Vascular Biology

Several cardiovascular risk factors have been described during the last decades. Postprandial hyperlipidemia has been recognized as an important factor contributing to atherogenesis; however chylomicron remnants have not been used widely in risk equations. One of the probable causes for this lack of consideration in clinical practice may be that the metabolism of chylomicrons and their remnants has been rather difficult to study and, more so, to modulate in vivo. The current issue of the International Journal of Vascular Medicine provides novel insight into the metabolic changes of chylomicrons and their remnants in relation to vascular damage. The paper by G. H. Tomkin and D. Owens “The chylomicron: relationship to atherosclerosis” provides an excellent overview of the molecular mechanisms involved in chylomicron synthesis and metabolism in humans. The paper by B. Klop et al. “Understanding postprandial inflammation and its relationship to lifestyle behaviour and metabolic diseases” describes novel aspects related to inflammation in different clinical conditions and under variable lifestyle situations. Following this line of inflammatory-dependent aspects of chylomicrons, the paper by M. Cao et al. “Dual AAV/IL-10 plus STAT3 anti-inflammatory gene delivery lowers atherosclerosis in LDLR KO mice, but without increased benefit” further explores aspects of cholesterol metabolism involving different molecular targets important for both hepatic and intestinal cholesterol metabolism. S. A. Lopez et al. proceed with a paper investigating the effects of oxidized chylomicron remnants on monocyte activation and the effects of the antioxidant drug probucol on this interaction “The oxidative state of chylomicron remnants influences their modulation of human monocyte activation.” L. D. Roche and et al. provide evidence suggesting that postprandial hypertriglyceridemia simulated by an infusion with artificial TG-rich lipoproteins (Lipofundin) induces oxidative stress and atherosclerotic lesions in an animal model prone to develop atherosclerosis “Lipofundin-induced hyperlipidemia promotes oxidative stress and atherosclerotic lesions in New Zealand white rabbits.” The paper by M. Napolitano et al. “Phospholipase A2 mediates apolipoprotein-independent uptake of chylomicron remnant-like particles by human macrophages” includes novel work showing that macrophage lipolytic enzymes mediate the internalization of postprandial TG-rich lipoproteins and that secretory phospholipase A2 (sPLA2) and cytosolic PLA2 play a more important role than extracellular lipoprotein lipase-mediated TG hydrolysis. M. M. Pallebage-Gamarallage et al. describe in the following investigation “A diet enriched in docosahexanoic acid exacerbates brain parenchymal extravasation of Apo B lipoproteins induced by chronic ingestion of saturated fats,” how dietary interventions can lead to modulation of cerebrovascular inflammation by oxidative stress. A. Van der Wiel provides a comprehensive update on the effects of alcohol ingestion on fasting and postprandial triglyceridemia “The effect of alcohol on postprandial and fasting triglycerides”, which is followed by a paper by B. Klop et al. “AT1 receptor gene polymorphisms in relation to postprandial lipemia” showing a novel relationship between polymorphisms of genes involved in the regulation of blood pressure with postprandial lipemia. J. P. H. van Wijk and M. Castro Cabezas contributed with an update on the effects of antiretroviral therapy in HIV-infected patients on TG metabolism “Hypertriglyceridemia, metabolic syndrome, and cardiovascular disease in HIV-infected patients: effects of antiretroviral therapy and adipose tissue distribution.” Finally, G. Charach et al. provided a review describing the effects of bile acid secretion and intestinal absorption on plasma lipoproteins and coronary atherosclerosis. M. Castro Cabezas Kathleen M. Botham John C. L. Mamo Spencer D. Proctor

Abstract 8252: Altered Metabolism of Post-Prandial Remnant Lipoprotein Fractions in Autosomal Recessive Hypercholesterolemia

Introduction: Autosomal recessive hypercholesterolemia (ARH) associated with mutations in LDLR adaptor protein 1 (LDLRAP1) gene is extremely rare disorder. Although this defect seems to be a phenocopy of homozygous familial hypercholesterolemia (FH), clinical phenotype of ARH seems less severe, more responsive to statins, the cause of which may be derived from the difference of remnant-like particles (RLP) clearance. Hypothesis: We assessed the hypothesis that the ability of RLP clearance of ARH subject was different from that of FH subject. Methods: OFTT cream (Jomo Shokuhin, Takasaki, Japan) 50 g was given per body surface area (squared meter), blood sampling was performed at 2 hour intervals up to 6 hour. Plasma lipoprotein and RLP fraction were determined by HPLC system in one ARH subject (68yr, LDL-C=286mg/dl), 4 heterozygous FH subjects (58±17yr, LDL-C=241±26mg/dl), and 4 controls (62±17yr, LDL-C=88±6mg/dl). All male subjects were selected to have apolipoprotein E2/E3 phenotype without diabetes. None of the subjects took medication known to affect plasma lipids at the time of this study for at least 4 weeks. The area under curve (AUC) of TG, RLP-TG, and RLP-cholesterol levels were evaluated. Results: After oral fat load, the AUC of TG, RLP-TG, and RLP-cholesterol levels of heterozygous FH subjects were significantly increased compared to those of controls (441±87 mg/dl*hour vs 316±133 mg/dl*hour, p&lt;0.05, 126±60 mg/dl*hour vs 49±11 mg/dl*hour, p&lt;0.05, 34±8 mg/dl*hour vs 23±11 mg/dl*hour, p&lt;0.05, respectively). In contrast to these results, the AUC of TG, RLP-TG, and RLP-cholesterol levels of ARH were within the nomal range (310mg/dl*hour, 23mg/dl*hour, 22mg/dl*hour, respectively). Conclusions: These results suggest that the lack of LDLRAP1 modulates RLP metabolism, activating an alternate pathway which can remove remnant fraction paradoxically. This preferred pathway should contribute to the greater responsiveness to statins. Our results will provide new insights into the lipoprotein metabolism of ARH and the novel pharmacological target for LDLRAP1.

Abstract 9322: Remnant Lipoproteinemia is a Predictor of Coronary Events in Patients with Coronary Artery Disease and Chronic Kidney Disease

Although triglyceride (TG) levels are increased in chronic kidney disease (CKD), the independence of high TG levels as a risk for coronary events remains debatable. We have previously shown that remnant lipoproteins, one of TG-rich lipoproteins, is a strong risk for future coronary events independent of low HDL-C levels and high LDL-C levels in patients with coronary artery disease (CAD). Thus, this study examined predictive value of remnant lipoproteins for coronary events in CAD patients with CKD. Methods: Fasting serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 229 patients with CAD and CKD (estimated GFR &lt; 60 ml/min/1.73m 2 , excluding hemodialysis patients). All patients were prospectively followed up for a period of 18 months or until occurrence of one of following events: cardiac death, nonfatal myocardial infarction (MI), unstable angina requiring unplanned coronary revascularization or worsening heart failure requiring hospitalization. Results: During follow-up period, events occurred in 28 (37%) patients with higher levels of RLP-C (&gt; 5.0 mg/dL, 75 th percentile of the distribution) (5 cardiac death, 4 MI, 15 unstable angina, 4 heart failure), while events occurred in 18 (11.7%) patients with lower RLP-C levels (&lt; 5.0 mg/dL) (2 MI, 14 unstable angina, 2 heart failure) (p&lt;0.0001). In Kaplan-Meier analysis, higher RLP-C levels resulted in a higher probability for the development of coronary events than lower RLP-C levels (p &lt; 0.01). In multivariate Cox proportional hazards analysis, higher RLP-C levels were a significant predictor of coronary events (HR 1.8, 95%CI 1.3 - 6.9, p &lt; 0.01), that was independent of TG levels and the Framingham risk variables. In c -statistics, RLP-C levels had an incremental effect on the predictive value of the Framingham risk variables for coronary events (area under ROC curve: RLP-C + Framingham risks 0.83 vs. Framingham risks alone 0.75, p &lt; 0.01). Conclusions: High remnant lipoprotein levels are an independent predictor of coronary events in CAD patients with CKD. Assessment of remnant lipoprotein levels may be useful for risk stratification for coronary events in patients with CKD.

Atorvastatin 10 mg plus ezetimibe 10 mg compared with atorvastatin 20 mg: Impact on the lipid profile in Japanese patients with abnormal glucose tolerance and coronary artery disease

Oxidized low-density lipoprotein (LDL) cholesterol is a sensitive lipid marker for predicting atherosclerosis. Ezetimibe and statins are reported to decrease both LDL cholesterol and oxidized LDL cholesterol. This prospective randomized open-label crossover study compared combination therapy with atorvastatin plus ezetimibe versus high-dose atorvastatin monotherapy. Changes in serum lipids, including malondialdehyde-modified LDL (MDA-LDL) as a representative form of oxidized LDL cholesterol, and glucose metabolism were assessed. The subjects were 39 Japanese patients with coronary artery disease and type 2 diabetes or impaired glucose tolerance who were taking 10 mg/day of atorvastatin (30 men and 9 women with a mean age of 67.8 years). They were randomized to a group that first received add-on ezetimibe (10 mg/day) or a group that first received atorvastatin monotherapy at a higher dose of 20 mg/day. Both treatments were given for 12 weeks each in a crossover fashion. Add-on ezetimibe significantly decreased MDA-LDL (109.0 ± 31.9 mg/dl to 87.7 ± 29.4 mg/dl, p=0.0009), while up-titration of atorvastatin did not. The decrease with add-on ezetimibe was significantly greater than with up-titration of atorvastatin (p=0.0006). Total cholesterol and LDL cholesterol were significantly decreased by both treatments, but the percent reduction with add-on ezetimibe was significantly greater (p<0.05). High-density lipoprotein cholesterol was significantly increased by both treatments and there was no significant difference between them. The apolipoprotein B/apolipoprotein A-I ratio and remnant-like particle cholesterol were only significantly decreased by add-on ezetimibe. Both treatments caused similar elevation of hemoglobin A(1c). In Japanese patients with type 2 diabetes or impaired glucose tolerance and coronary artery disease, adding ezetimibe (10 mg/day) to atorvastatin (10 mg/day) significantly improved the lipid profile compared with atorvastatin monotherapy at 20 mg/day.

Comparative reactivity of remnant-like lipoprotein particles (RLP) and low-density lipoprotein (LDL) to LDL receptor and VLDL receptor: Effect of a high-dose statin on VLDL receptor expression

Background Comparison of the reactivity of remnant-like lipoprotein particles (RLP) and LDL particles to LDL receptor and VLDL receptor has not been investigated. Methods LDL receptor- or VLDL receptor-transfected ldlA-7, HepG2 and L6 cells were used. Human LDL and rabbit β-VLDL were isolated by ultracentrifugation. Human RLP was isolated using an immunoaffinity mixed gel. The effect of statin on lipoprotein receptors was examined. Results Both LDL receptor and VLDL receptor recognized RLP. In LDL receptor transfectants, RLP, β-VLDL and LDL all bound to LDL receptor. Cold RLP competed efficiently with DiI-β-VLDL; however, cold LDL competed weakly. In VLDL receptor transfectants, RLP and β-VLDL bound to VLDL receptor, but not LDL. RLP bound to VLDL receptor with higher affinity than β-VLDL because of higher apolipoprotein E in RLP. LDL receptor expression was induced in HepG2 by the low concentration of statin while VLDL receptor expression was induced in L6 myoblasts at higher concentration. Conclusions RLP are bound to hepatic LDL receptor more efficiently than LDL, which may explain the mechanism by which statins prevent cardiovascular risk by primarily reducing plasma RLP rather than by reducing LDL. Additionally, a high-dose of statins also may reduce plasma RLP through muscular VLDL receptor.

Effect of Ezetimibe on Remnant-Like Particle Cholesterol in Subjects with Metabolic Syndrome

Objective: To investigate the influence of ezetimibe monotherapy on remnant-like particle cholesterol (RLP-C) in subjects with metabolic syndrome (MetS). Materials and Methods: Ezetimibe (10 mg/daily) was prescribed over a 12-week period for hypercholesterolemic subjects divided into groups with MetS (n = 28; male/female = 13/15; mean age 67 years) and without MetS (n = 22; male/female = 9/13; mean age 66 years). In the pre- and post-treatment phases, BMI, blood pressure and fasting blood levels of glucose, lipid panels and RLP-C were measured. Results: The group with MetS showed significantly higher RLP-C levels than the group without MetS [median level: 0.18 vs. 0.12 mmol/l (7.1 vs. 4.4 mg/dl), p < 0.01] in the pre-treatment phase. In the post-treatment phase, the low-density lipoprotein cholesterol levels were significantly reduced in both groups to a similar level (p < 0.001 in both), while there was a significantly greater reduction in RLP-C in the group with MetS than the group without MetS [median level: 0.12 vs. 0.11 mmol/l (4.8 vs. 4.1 mg/dl), p < 0.05]. This difference in RLP-C remained significant after adjusting for confounding factors. Conclusion: Ezetimibe monotherapy may be associated with a greater reduction in RLP-C levels in subjects with MetS than in those without MetS.

Phospholipase A2 Mediates Apolipoprotein-Independent Uptake of Chylomicron Remnant-Like Particles by Human Macrophages

Apolipoprotein E-receptor-mediated pathways are the main routes by which macrophages take up chylomicron remnants, but uptake may also be mediated by receptor-independent routes. To investigate these mechanisms, triacylglycerol (TG) accumulation induced by apolipoprotein-free chylomicron remnant-like particles (CRLPw/o) in human monocyte-derived macrophages was evaluated. Macrophage TG content increased about 5-fold after incubation with CRLPw/o, and this effect was not reduced by the inhibition of phagocytosis, macropinocytosis, apolipoprotein E function, or proteoglycan bridging. The role of lipases, including lipoprotein lipase, cholesteryl ester hydrolase, and secretory (sPLA2) and cytosolic phospholipase A2, was studied using [3H]TG-labelled CRLPw/o. Total cell radioactivity after incubation with [3H]TG CRLPw/o was reduced by 15–30% by inhibitors of lipoprotein lipase and cholesteryl ester hydrolase and by about 45% by inhibitors of sPLA2 and cytosolic PLA2 . These results suggest that macrophage lipolytic enzymes mediate the internalization of postprandial TG-rich lipoproteins and that sPLA2 and cytosolic PLA2, play a more important role than extracellular lipoprotein lipase-mediated TG hydrolysis.

Remnant-like particle cholesterol and serum amyloid A–low-density lipoprotein levels in obese subjects with metabolic syndrome

Although the circulating levels of remnant-like particle cholesterol (RLP-C) or serum amyloid A-low-density lipoprotein (SAA-LDL) can individually be increased in subjects with metabolic syndrome (MetS), the correlation between the two markers has not yet been previously studied. In the present study, we aimed to investigate the correlation between RLP-C and SAA-LDL in obese subjects with MetS in comparison to those without MetS. A total of 436 obese subjects were divided into groups with MetS and without MetS (male/female 75/143, mean age 49 years, current smokers 16% in both groups) by applying the age-, gender-, and smoking habit-matching method based on the database in the multicenter Japan Obesity and Metabolic Syndrome Study (JOMS). The data, including RLP-C and SAA-LDL, were compared in each group. Significantly greater levels of RLP-C or SAA-LDL were observed in subjects with MetS in comparison with those without MetS. There was a significantly positive correlation between RLP-C and SAA-LDL, with a relatively greater correlation in subjects with MetS (coefficient= 0.290, P<.01) in comparison with those without MetS (coefficient= 0.181, P < .01). Multivariate-adjusted correlation analyses showed a greater correlation between RLP-C and SAA-LDL in subjects with MetS, relative to those without MetS, although the significant correlation decreased in both groups when the hypertriglyceridemic states were taken into account. A relatively greater and positive correlation between greater levels of RLP-C and SAA-LDL in obese subjects with MetS, in comparison with those without MetS, may be linked to the development of MetS-related cardiovascular disease.