The effect of statin alone or in combination with ezetimibe on postprandial lipoprotein composition in obese metabolic syndrome patients

Introduction: Fasting and postprandial hypertriglyceridemia are essential features of metabolic syndrome. Statins decrease fasting lipid levels but fail to reduce fat load induced hypertriglyceridemia. We established whether ezetimibe combined with simvastatin differently influences post fat load lipid levels and lipoprotein composition its compared to simvastatin 80 mg monotherapy in obese male metabolic syndrome patients. Methods: Prospective. randomized. double blind. crossover trial. Male obese metabolic syndrome (ATPIII) patients (n = 19) were treated with simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg for 6 weeks. At the start of the Study and after each treatment period oral fat loading, tests were performed. Lipoprotein fractions (triglyceride-rich lipoproteins (TRL), IDL, LDL, and HDL) were isolated by density gradient ultracentrifugation. Postprandial changes in lipid levels were integrated as areas under the curve (AUCs). Results: Fasting LDL-C RLP-C and triglycerides were lowered equally by both simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg Also postprandial plasma triglyceride levels (net AUC-TG) were equally lowered after both treatments (5.16 +/- 0.50 mmol h/l after simvastatin/ezetimibe 10 mg/10 mg and 6.09 +/- 0.71 mmol h/l after simvastatin 80 mg) compared to fat loading Without treatment (6.64 +/- 0.86 mmol h/l). In addition. triglyceride-content in lipoprotein fractions after fat load (net AUCs) were also equally reduced after both treatments. Similarly, TRL. IDL and LDL cholesterol and apoB concentrations were equally affected by both treatment regimens. leading to a reduced number of circulating particles, in both conditions. However the composition of these particles remained the same. Conclusion: Simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg were equally effective in reducing fasting and post fat load plasma lipid, and lipoprotein concentrations and lipoprotein composition in obese metabolic syndrome patients. (C) 2008 Elsevier Ireland Ltd. All rights reserve

Lipid-lowering therapy does not affect the postprandial drop in high density lipoprotein-cholesterol (HDL-c) plasma levels in obese men with metabolic syndrome: a randomized double blind crossover trial

INTRODUCTION: The postprandial lipid metabolism in metabolic syndrome patients is disturbed and may add to the increased cardiovascular risk in these patients. It is not known whether postprandial high density lipoprotein-cholesterol (HDL-c) metabolism is also affected and whether this can be influenced by statin and/or ezetimibe treatment. METHODS: Prospective, randomized, double blind, crossover trial comparing simvastatin 80 mg with simvastatin/ezetimibe 10 mg/10 mg treatment for 6 weeks on postprandial HDL-c metabolism in 15, nonsmoking, male, obese metabolic syndrome patients (Adult Treatment Panel III, ATPIII). Only study medication was allowed. HDL-c concentrations, cholesteryl ester transfer (CET), CET protein (CETP) mass and adiponectin were measured before and after oral fat loading. ClinicalTrials.gov NCT00189085. RESULTS: Plasma HDL-c levels remained stable during continuous fasting following an overnight fast. Pre-fat load HDL-c concentrations without treatment, after simvastatin and simvastatin/ezetimibe treatment were 1.15 +/- 0.04, 1.16 +/- 0.05 and 1.11 +/- 0.04 mmol/l. Fat load induced a 11% drop in HDL-c plasma levels; 1.02 +/- 0.05 mmol/l (P < 0.001) which was not affected by either therapy. Triglyceride levels during fat load were similar after both treatments. Total CET increased from 9.73 +/- 0.70 to 12.20 +/- 0.67 nmol/ml/h (P = 0.004). Four hours after fat loading CETP mass was increased while adiponectin levels were decreased, irrespective of treatment. DISCUSSION: HDL-c levels decrease as CET increases after fat loading in obese metabolic syndrome patients. This is not influenced by either simvastatin or simvastatin/ezetimibe treatment. After fat loading, CETP mass and CET increased, and adiponectin decreased pointing towards a potential role for intra-abdominal fat. Decreased postprandial HDL-c levels may contribute to the increased cardiovascular risk in metabolic syndrome patients on top of already low HDL-c level

Appraisal of hepatic lipase and lipoprotein lipase activities in mice

A variety of methods are currently used to analyze HL and LPL activities in mice. In search of a simple methodology, we analyzed mouse preheparin and postheparin plasma LPL and HL activities using specific polyclonal antibodies raised in rabbit against rat HL (anti-HL) and in goat against rat LPL (anti-LPL). As an alternative, we analyzed HL activity in the presence of 1 M NaCl, a condition known to inhibit LPL activity in humans. The assays were validated using plasma samples from wild-type and HL-deficient C57BL/6 mice. We now show that the use of 1 M NaCl for the inhibition of plasma LPL activity in mice may generate incorrect measurements of both LPL and HL activities. Our data indicate that HL can be measured directly, without heparin injection, in preheparin plasma, because virtually all HL is present in an unbound form circulating in plasma. In contrast, measurable LPL activity is present only in postheparin plasma. Both HL and LPL can be measured using the same assay conditions (low salt and the presence of apolipoprotein C-II as an LPL activator). Total lipase activity in postheparin plasma minus preheparin HL activity reflects LPL activity. Specific antibodies are not required

Red wine extract protects against oxidative-stress-induced endothelial senescence

Red wine polyphenols may preserve endothelial function during aging. Endothelial cell senescence enhances age-related endothelial dysfunction. We investigated whether RWE (red wine extract) prevents oxidative-stress-induced senescence in HUVECs (human umbilical-vein endothelial cells). Senescence was induced by exposing HUVECs to tBHP (t-butylhydroperoxide), and quantified by senescence-associated beta-galactosidase staining. RWE (0-50 mu g/ml) concentration dependently decreased senescence by maximally 33 +/- 7.1 %. RWE prevented the senescence-associated increase in p21 protein expression, inhibited tBHP-induced DNA damage of endothelial cells and induced relaxation of PCAs (porcine coronary arteries). Inhibition of SIRT1 (sirtuin 1) by sirtinol partially reversed the effect of RWE on tBHP-induced senescence, whereas both the NOS (nitric oxide synthase) inhibitor L-NMMA (N-G-monomethyl-L-arginine) and the COX (cyclooxygenase) inhibitor indomethacin fully inhibited it. Furthermore, incubation of HUVECs with RWE increased eNOS (endothelial NOS) and COX-2 mRNA levels as well as phosphorylation of eNOS at Ser(1177). RWE protects endothelial cells from tBHP-induced senescence. NO and COX-2, in addition to activation of SIRT1, play a critical role in the inhibition of senescence induction in human endothelial cells by RWE