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Context: Hypercatabolism of high-density lipoprotein (HDL) apolipoprotein (apo) A-I results in low plasma apoA-I concentration. The mechanisms regulating apoA-I catabolism may relate to alterations in very low density lipoprotein (VLDL) metabolism and plasma adiponectin and serum amyloid A protein (SAA) concentrations.Objective: We examined the associations between the fractional catabolic rate (FCR) of HDL-apoA-I and VLDL kinetics, plasma adiponectin, and SAA concentrations.Study Design: The kinetics of HDL-apoA-I and VLDL-apoB were measured in 50 obese and 37 nonobese men using stable isotopic techniques.Results: In the obese group, HDL-apoA-I FCR was positively correlated with insulin, homeostasis model of assessment for insulin resistance (HOMA-IR) score, triglycerides, VLDL-apoB, and VLDL-apoB production rate (PR). In the nonobese group, HDL-apoA-I FCR was positively correlated with triglycerides, apoC-III, VLDL-apoB, and VLDL-apoB PR and negatively correlated with plasma adiponectin. Plasma SAA was not associated with HDL-apoA-I FCR in either group. In multiple regression analyses, VLDL-apoB PR and HOMA-IR score, and VLDL-apoB PR and adiponectin were independently predictive of HDL-apoA-I FCR in the obese and nonobese groups, respectively. HDL-apoA-I FCR was positively and strongly associated with HDL-apoA-I PR in both groups.Conclusions: Variation in VLDL-apoB production, and hence plasma triglyceride concentrations, exerts a major effect on the catabolism of HDL-apoA-I. Insulin resistance and adiponectin may also contribute to the variation in HDL-apoA-I catabolism in obese and nonobese subjects, respectively. We also hypothesize that apoA-I PR determines a steady-state, lowered plasma of apoA-I, which may reflect a compensatory response to a primary defect in the catabolism of HDL-apoA-I due to altered VLDL metabolism.

Objectives— The metabolic syndrome (MetS) is characterized by insulin resistance and dyslipidemia that may accelerate atherosclerosis. Disturbed apolipoprotein (apo) C-III metabolism may account for dyslipidemia in these subjects. Atorvastatin and fenofibrate decrease plasma apoC-III, but the underlying mechanisms are not fully understood. Methods and Results— The effects of atorvastatin (40 mg/d) and fenofibrate (200 mg/d) on the kinetics of very-low density lipoprotein (VLDL)-apoC-III were investigated in a crossover trial of 11 MetS men. VLDL-apoC-III kinetics were studied, after intravenous d 3 -leucine administration using gas chromatography-mass spectrometry and compartmental modeling. Compared with placebo, both atorvastatin and fenofibrate significantly decreased ( P P Conclusions— Both atorvastatin and fenofibrate have dual regulatory effects on VLDL-apoC-III kinetics in MetS; reduced production and increased fractional catabolism of VLDL-apoC-III may explain the triglyceride-lowering effect of these agents.

The aim of this study was to observe the changes in glucose metabolism after antipsychotic (APS) therapy, to note the influencing factors, as well as to discuss the relationship between the occurrence of glucose metabolism disorders of APS origin and abnormal glycosylated hemoglobin (HbA1c) levels. One hundred and fifty-two patients with schizophrenia, whose fasting plasma glucose (FPG) and 2-h plasma glucose (2hPG) in the oral glucose tolerance test (2HPG) were normal, were grouped according to the HbA1c levels, one normal and the other abnormal, and were randomly enrolled into risperidone, clozapine and chlorpromazine treatment for six weeks. The FPG and 2hPG were measured at the baseline and at the end of the study. In the group with abnormal HbA1c and clozapine therapy, 2HPG was higher after the study [(9.5 ± 1.8) mmol/L] than that before the study [(7.2 ± 1.4) mmol/L] and the difference was statistically significant (P0.01). FPG had no statistically significant difference before and after the study in any group (P0.05). HbA1c levels and drugs contributing to 2HPG at the end of study had statistical cross-action (P0.01). In the abnormal HbA1c group, 2HPG after the study was higher in the clozapine treatment group [(9.5 ± 1.8) mmol/L] than in the risperidone treatment group [(7.4 ± 1.7) mmol/L] and the chlorpromazine treatment group [(7.3 ± 1.6) mmol/L]. The differences were statistically significant (P0.01). In the normal HbA1c group there was no statistically significant difference before and after the study in any group (P0.05). 2HPG before [(7.1 ± 1.6) mmol/L] and after the study [(8.1 ± 1.9) mmol/L] was higher in the abnormal HbA1c group than in the normal HbA1c group [(6.2 ± 1.4) mmol/L vs (6.5 ± 1.4) mmol/L] with the difference being statistically significant (P0.01 vs P0.001). As compared with normal HbA1c group, the relative risk (RR) of glucose metabolism disease occurrence was 4.7 in the abnormal HbA1c group with the difference being statistically significant (P0.001). Patients with abnormal HbA1c are more likely to have a higher risk of having glucose metabolism disorders after APS treatment.

Summary Objective Phospholipid transfer protein (PLTP) is an important regulator in the transport of surface components of triglyceride-rich lipoprotein (TRL) to high density lipoprotein (HDL) during lipolysis and may therefore play an important role in regulating HDL transport. In this study we investigated the relationship of plasma PLTP activity with HDL metabolism in men. Design and methods The kinetics of HDL LpA-I and LpA-I:A-II were measured using intravenous administration of [d3]-leucine, gas chromatography–mass spectrometry (GCMS) and a new multicompartmental model for HDL subpopulation kinetics (SAAM II) in 31 men with wide-ranging body mass index (BMI 18–46 kg/m2). Plasma PLTP activity was determined as the transfer of radiolabelled phosphatidylcholine from small unilamellar phosphatidylcholine vesicles to ultracentrifugally isolated HDL. Results PLTP activity was inversely associated with LpA-I concentration and production rate (PR) after adjusting for insulin resistance (P

Reduced high density lipoprotein (HDL) concentration in the metabolic syndrome (MetS) is associated with increased risk of diabetes and cardiovascular disease and is related to defects in the kinetics of HDL apolipoprotein (apo) A-I and A-II.The objective of the study was to investigate HDL apoA-I and apoA-II kinetics in nondiabetic men with MetS and lean controls by developing a model that describes the kinetics of lipoprotein (Lp)A-I and LpA-I:A-II particles.Twenty-three MetS men and 10 age-matched lean controls were investigated. ApoA-I and apoA-II tracer/tracee ratios were studied after iv d3-leucine administration using gas chromatography mass spectrometry.Compared with lean subjects, MetS subjects had accelerated catabolism of LpA-I (P0.001), LpA-I:A-II (P = 0.005), and apoA-II (P = 0.005); the production rate of LpA-I was also significantly elevated in MetS, so that the dominant changes in plasma concentrations were reduction in LpA-I:A-II (P0.001) and apoA-II (P0.05). Increased catabolism of LpA-I and LpA-I:A-II was directly related to increased waist circumference, hypertriglyceridemia, low HDL-cholesterol, small HDL particle size, hyperinsulinemia, and low phospholipid transfer protein (PLTP) activity; overproduction of LpA-I was significantly associated with increased waist circumference, insulin resistance, and low PLTP activity.MetS men exhibit hypercatabolism of the two major HDL lipoprotein particles, LpA-I and LpA-I:A-II, but selective overproduction of LpA-I maintains a normal plasma concentration of LpA-I. These kinetic perturbations are probably related to central obesity, insulin resistance, hypertriglyceridemia, and low plasma PLTP activity.

A common polymorphism in the hepatic lipase (HL) gene promoter, -514C/T, affecting enzyme activity, has been associated with alterations in plasma lipoprotein levels. However a relationship with coronary heart disease (CHD) is less well documented.We studied HL -514 C/T in 562 Caucasian CHD patients aged under 50 years and in 642 Caucasian community recruited subjects without historical evidence of CHD.Male CHD subjects (n = 490) had a 41% carrier rate for the C to T substitution, compared with 33% in corresponding controls (n = 330), [OR = 1.42 (95% CI:1.06-1.90), P0.02], T allele frequencies being 0.231 and 0.177 respectively [OR = 1.39 (1.08-1.78), P0.01]. In male CHD subjects, the T allele was associated with higher HDL-cholesterol (HDL-C) (CC: 0.95 +/- 0.24 (SD); CT: 1.04 +/- 0.41; TT: 1.01 +/- 0.20 mmol/l, P = 0.02, ANOVA) but the trend was not significant in females. In male CHD patients the T allele was more frequently encountered in those with high (4.5 mmol/l) than in those with low triglycerides [68% vs. 39%, OR = 3.13 (1.54-6.67), P = 0.001]. In community control subjects, the T allele was associated with a trend to higher HDL-C levels, the significance varying between subgroups while, in males, serum total and LDL-cholesterol were significantly lower in T homozygotes than in the other two genotypes (LDL-C: 2.73 +/- 0.63 vs. 3.56 +/- 0.95 mmol/l; P = 0.01). During the course of this study, a previously unreported promoter region polymorphism was found exclusively on -514C chromosomes (-592A/G, A allele frequency 0.108, 95% CI 0.09 - 0.126). It can lead to mistyping of C as T alleles in C/T heterozygotes, resulting in overestimation of -514 T homozygotes.The T allele of the hepatic lipase -514 C/T polymorphism is associated with changes in plasma lipids. The superficially paradoxical predisposition to CHD in males is attributable to impairment of TG rich lipoprotein metabolism and reverse cholesterol transport.

OBJECTIVE Subjects with the metabolic syndrome have reduced HDL cholesterol concentration and altered metabolism of high-density lipoprotein (Lp)A-I and LpA-I:A-II particles. In the metabolic syndrome, fenofibrate and atorvastatin may have differential effects on HDL particle kinetics. RESEARCH DESIGN AND METHODS Eleven men with metabolic syndrome were studied in a randomized, double-blind, crossover trial of 5-week intervention periods with placebo, fenofibrate (200 mg/day), and atorvastatin (40 mg/day). LpA-I and LpA-I:A-II kinetics were examined using stable isotopic techniques and compartmental modeling. RESULTS Compared with placebo, fenofibrate significantly increased the production of both LpA-I:A-II (30% increase; P < 0.001) and apoA-II (43% increase; P < 0.001), accounting for significant increases of their corresponding plasma concentrations (10 and 23% increases, respectively), but it did not alter LpA-I kinetics or concentration. Atorvastatin did not significantly alter HDL concentration or the kinetics of HDL particles. CONCLUSIONS In the metabolic syndrome, fenofibrate, but not atorvastatin, influences HDL metabolism by increasing the transport of LpA-I:A-II particles.

The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d3-leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased (P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL2 cholesterol (P < 0.001), HDL3 cholesterol (P < 0.01), apoAI (P = 0.01), and apoAII (P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased (P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production (P < 0.001) and FCR (P = 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome.