apoA-II Production Research Articles

Mechanism of Action of a Peroxisome Proliferator-Activated Receptor (PPAR)-δ Agonist on Lipoprotein Metabolism in Dyslipidemic Subjects with Central Obesity

Dyslipidemia increases the risk of cardiovascular disease in obesity. Peroxisome proliferator-activated receptor (PPAR)-δ agonists decrease plasma triglycerides and increase high-density lipoprotein (HDL)-cholesterol in humans. The aim of the study was to examine the effect of GW501516, a PPAR-δ agonist, on lipoprotein metabolism. Design, Setting, and Intervention: We conducted a randomized, double-blind, crossover trial of 6-wk intervention periods with placebo or GW501516 (2.5 mg/d), with 2-wk placebo washout between treatment periods. We recruited 13 dyslipidemic men with central obesity from the general community. We measured the kinetics of very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein-, and low-density lipoprotein (LDL)-apolipoprotein (apo) B-100, plasma apoC-III, and high-density lipoprotein (HDL) particles (LpA-I and LpA-I:A-II). GW501516 decreased plasma triglycerides, fatty acid, apoB-100, and apoB-48 concentrations. GW501516 decreased the concentrations of VLDL-apoB by increasing its fractional catabolism and of apoC-III by decreasing its production rate (P < 0.05). GW501516 reduced VLDL-to-LDL conversion and LDL-apoB production. GW501516 increased HDL-cholesterol, apoA-II, and LpA-I:A-II concentrations by increasing apoA-II and LpA-I:A-II production (P < 0.05). GW501516 decreased cholesteryl ester transfer protein activity, and this was paralleled by falls in the triglyceride content of VLDL, LDL, and HDL and the cholesterol content of VLDL and LDL. GW501516 increased the hepatic removal of VLDL particles, which might have resulted from decreased apoC-III concentration. GW501516 increased apoA-II production, resulting in an increased concentration of LpA-I:A-II particles. This study elucidates the mechanism of action of this PPAR-δ agonist on lipoprotein metabolism and supports its potential use in treating dyslipidemia in obesity.

Apolipoprotein A-II and adiponectin as determinants of very low-density lipoprotein apolipoprotein B-100 metabolism in nonobese men

Data from cellular systems and transgenic animal models suggest a role of apolipoprotein (apo) A-II in the regulation of very low-density lipoprotein (VLDL) metabolism. However, the precise mechanism whereby apoA-II regulates VLDL metabolism remains to be elucidated in humans. In this study, we examined the associations between the kinetics of high-density lipoprotein (HDL)-apoA-II and VLDL-apoB-100 kinetics, and plasma adiponectin concentrations. The kinetics of HDL-apoA-II and VLDL-apoB-100 were measured in 37 nonobese men using stable isotope techniques. Plasma adiponectin concentration was measured using immunoassays. Total plasma apoA-II concentration was positively associated with HDL-apoA-II production rate (PR) (r = 0.734, P < .01); both were positively associated with plasma triglyceride concentration (r = 0.360 and 0.369, respectively) and VLDL-apoB-100 PR (r = 0.406 and 0.427, respectively), and inversely associated with plasma adiponectin concentration (r = -0.449 and -0.375, respectively). Plasma adiponectin was inversely associated with plasma triglyceride concentration (r = -0.327), VLDL-apoB-100 concentration (r = -0.337), and VLDL-apoB-100 PR (r = -0.373). In multiple regression models including waist circumference and plasma insulin, plasma adiponectin concentration was an independent determinant of total plasma apoA-II concentration (β-coefficient = -0.508, P = .001) and HDL-apoA-II PR (β-coefficient = -0.374, P = .03). Conversely, total plasma apoA-II concentration (β-coefficient = 0.348, P = .047) and HDL-apoA-II PR (β-coefficient = -0.350, P = .035) were both independent determinants of VLDL-apoB-100 PR. However, these associations were not independent of plasma adiponectin. Variation in HDL apoA-II production, and hence total plasma apoA-II concentration, may exert a major effect on VLDL-apoB-100 production. Plasma adiponectin may also contribute to the variation in VLDL-apoB-100 production partly by regulating apoA-II transport.

Effect of rosiglitazone on HDL metabolism in subjects with metabolic syndrome and low HDL

Treatment with the peroxisome proliferator-activated receptor γ agonist rosiglitazone has been reported to increase HDL-cholesterol (HDL-C) levels, although the mechanism responsible for this is unknown. We sought to determine the effect of rosiglitazone on HDL apolipoprotein A-I (apoA-I) and apoA-II metabolism in subjects with metabolic syndrome and low HDL-C. Subjects were treated with placebo followed by rosiglitazone (8 mg) once daily. At the end of each 8 week treatment, subjects (n = 15) underwent a kinetic study to measure apoA-I and apoA-II production rate (PR) and fractional catabolic rate. Rosiglitazone significantly reduced fasting insulin and high-sensitivity C-reactive protein (hsCRP) and increased apoA-II levels. Mean apoA-I and HDL-C levels were unchanged following rosiglitazone treatment, although there was considerable individual variability in the HDL-C response. Rosiglitazone had no effect on apoA-I metabolism, whereas the apoA-II PR was increased by 23%. The change in HDL-C in response to rosiglitazone was significantly correlated with the change in apoA-II concentration but not to changes in apoA-I, measures of glucose homeostasis, or hsCRP. Treatment with rosiglitazone significantly increased apoA-II production in subjects with metabolic syndrome and low HDL-C but had no effect on apoA-I metabolism. The change in HDL-C in response to rosiglitazone treatment was unrelated to effects on apoA-I, instead being related to the change in the metabolism of apoA-II.

Association of apolipoprotein M with high-density lipoprotein kinetics in overweight-obese men

ObjectiveThe aim of this study was to investigate associations between plasma apoM concentration and HDL apoA-I and apoA-II kinetics in 60 overweight-obese, insulin resistant men. MethodsPlasma apoM concentration was determined using a sandwich ELISA with two monoclonal antibodies (CV<5%). The kinetics of HDL apoA-I and apoA-II were measured using intravenous administration of D3-leucine, gas chromatography–mass spectrometry and multi-compartmental modeling. ResultsPlasma apoM was inversely associated with body mass index and positively associated with plasma total cholesterol, LDL cholesterol and HDL cholesterol (p<0.05). There were no associations between plasma apoM and plasma triglyceride, NEFA, insulin, glucose, HOMA score or adiponectin concentrations. Plasma apoM was positively associated with both apoA-I and apoA-II concentrations (r=0.406, p<0.01 and r=0.510, p<0.01, respectively) and negatively associated with HDL apoA-I and apoA-II fractional catabolic rate (FCR) (r=−0.291, p=0.03 and r=−0.291, p=0.026, respectively). No significant associations were observed between plasma apoM and HDL apoA-I and apoA-II production rate. In multivariate regression models, both plasma apoM and triglycerides were significant, independent predictors of HDL apoA-I FCR (adjusted R2=16%, p<0.01) and HDL apoA-II FCR (adjusted R2=14%, p<0.01). ConclusionApoM may be a significant, independent predictor of HDL apoA-I and apoA-II catabolism in overweight-obese, insulin resistant men.

Effects of cholesteryl ester transfer protein inhibition on apolipoprotein A-II-containing HDL subspecies and apolipoprotein A-II metabolism

This study was designed to establish the mechanism responsible for the increased apolipoprotein (apo) A-II levels caused by the cholesteryl ester transfer protein inhibitor torcetrapib. Nineteen subjects with low HDL cholesterol (<40 mg/dl), nine of whom were also treated with 20 mg of atorvastatin daily, received placebo for 4 weeks, followed by 120 mg of torcetrapib daily for the next 4 weeks. Six subjects in the nonatorvastatin cohort participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks. At the end of each phase, subjects underwent a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine to determine the kinetics of HDL apoA-II. Relative to placebo, torcetrapib significantly increased apoA-II concentrations by reducing HDL apoA-II catabolism in the atorvastatin (-9.4%, P < 0.003) and nonatorvastatin once- (-9.9%, P = 0.02) and twice- (-13.2%, P = 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the alpha-2-migrating subpopulation of HDL when given as monotherapy (27%, P < 0.02; 57%, P < 0.003) or on a background of atorvastatin (28%, P < 0.01). In contrast, torcetrapib reduced concentrations of apoA-II in alpha-3-migrating HDL, with mean reductions of -14% (P = 0.23), -18% (P < 0.02), and -18% (P < 0.01) noted during the atorvastatin and nonatorvastatin 120 mg once- and twice-daily phases, respectively. Our findings indicate that CETP inhibition increases plasma concentrations of apoA-II by delaying HDL apoA-II catabolism and significantly alters the remodeling of apoA-II-containing HDL subpopulations.

Potent and Selective PPAR-α Agonist LY518674 Upregulates Both ApoA-I Production and Catabolism in Human Subjects With the Metabolic Syndrome

The study of PPAR-alpha activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-alpha agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-alpha agonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C). Subjects were randomized to receive LY518674 (100 microg) once daily (n=13) or placebo (n=15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C (-38%, P=0.002) and triglyceride (-23%, P=0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (-12%, P=0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% (P<0.0001), but this was accompanied by a 33% increase in the apoA-I FCR (P=0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate (P<0.0001) accompanied by a 25% increase in the FCR (P<0.0001), resulting in a significant increase in plasma apoA-II. Activation of PPAR-alpha with LY518674 (100 microg) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined.

Pioglitazone Stimulates Apolipoprotein A-I Production Without Affecting HDL Removal in HepG2 Cells

Pioglitazone, an antihyperglycemic drug, increases plasma high-density lipoprotein (HDL)-cholesterol in patients with type 2 diabetes. The mechanisms by which pioglitazone regulate HDL levels are not clear. This study examined the effect of pioglitazone on hepatocyte apolipoprotein AI (apoA-I) and apoA-II production and HDL-protein/cholesterol ester uptake. In human hepatoblastoma (HepG2) cells, pioglitazone, dose-dependently (0.5 to 10 micromol/L), increased the de novo synthesis (up to 45%), secretion (up to 44%), and mRNA expression (up to 59%) of apoA-I. Pioglitazone also increased apoA-II de novo synthesis (up to 73%) and mRNA expression (up to 129%). Pioglitazone did not affect the uptake of HDL3-protein or HDL3-cholesterol ester in HepG2 cells. The pioglitazone-induced apoA-I lipoprotein particles increased cholesterol efflux from THP-1 macrophages. The pioglitazone-induced apoA-I secretion or mRNA expression by the HepG2 cells was abrogated with the suppression of PPAR-alpha by small interfering RNA or a specific inhibitor of PPAR-alpha, MK886. The data indicate that pioglitazone increases HDL by stimulating the de novo hepatic synthesis of apoA-I without affecting hepatic HDL-protein or HDL-cholesterol removal. We suggest that pioglitazone-mediated hepatic activation of PPAR-alpha may be one of the mechanisms of action of pioglitazone to raise hepatic apoA-I and HDL.

Anti-hyperlipidemic properties of CM108 (a flavone derivative) in vitro and in vivo

Peroxisome proliferator-activated receptors (PPARs) and liver X receptor α are ligand-activated transcription factors that belong to nuclear receptors superfamily and are involved in the regulation of lipid metabolism. PPAR, especially PPAR-α, PPAR-γ agonists and liver X receptor α agonists can regulate the expression or biosynthesis of some factors involved in the formation and function of HDL, such as apolipoprotein (apo) A-I and ATP binding cassette transporter A1 (ABCA1). It is well known that HDL plays an important role in the treatment of hyperlipidemia as the carrier of reverse cholesterol transport. In the present study, the anti-hyperlipidemic properties of CM108, a derivative of flavone, 9-Hydroxy-2-mercapto-6-phenyl-2-thioxo-1,3,5-trioxa-2 λ 5-phospha-cyclopenta[ b]naphthalen-8-one, were studied. Through the transactivation assays of in vitro study, it was discovered that CM108 could activate PPAR-α PPAR-γ and liver X receptor α at 40–150 μg/ml, which subsequently resulted in activating ABCA1 promoter and enhancing apoA-I and apoA-II production, whereas reducing apoC-III production significantly. Furthermore, after in vivo study that the hyperlipidemic rats were treated with CM108 for 4 weeks, a significant increase was found in HDL cholesterol levels (26.7%, P < 0.05) and a significant decrease was also noticed in triglyceride levels (26.3%, P < 0.01) at 100 mg/kg CM108 group compared with that of control animals. Meanwhile, the atherogenicity index, represented by total cholesterol/HDL ratio, was significantly reduced ( P < 0.01). In conclusion, CM108 can effectively elevate HDL levels and lower triglyceride levels in hyperlipidemic rats maybe by regulating a series of genes, receptors and proteins related to HDL.

Different VLDL apo B, and HDL apo AI and apo AII metabolism in two heterozygous carriers of unrelated mutations in the lipoprotein lipase gene

Background Lipoprotein lipase (LPL) deficiency has been suggested as a cause of low HDL-cholesterol (HDL-C) plasma levels, by a mechanism that involves an enhanced catabolism of HDL apolipoprotein (apo) AI. To verify the role of 2 different LPL gene mutations on HDL metabolism, we studied the in vivo turnover of the apo AI and apo AII in heterozygous carriers of LPL deficiency. Methods Apo AI and AII kinetics were studied by a 10-h primed constant infusion of 5,5,5- 2H 3-leucine approach in 2 carriers, 1 man (patient 1) and 1 woman (patient 2), and 5 control subjects. The rates of HDL apolipoproteins production (PR) and catabolism (FCR) were estimated using a one-compartment model-based analysis. Results Both carriers had low HDL-C plasma levels and only patient 1 was hypertriglyceridemic. VLDL apo B was 4-times slower in patient 1 as compared to patient 2. The FCRs of apo AI in both carriers was within the range of the controls (0.200, 0.221 and 0.211 ± 0.051 day − 1 , respectively). Apo AII FCR in patient 1 was about 20% lower than the mean of the control group whereas being normal in patient 2. Apo AI PR in patient 1 (9.20 mg kg − 1 day − 1 ) was below the lowest value in controls (range, 10.52–13.24 mg kg − 1 day − 1 ) whereas in patient 2 it was normal. Apo AII PR in both patients was similar to controls. Conclusion The heterozygous carriers of 2 different mutations in the LPL gene had different VLDL apo B FCR, and from normal to slightly low HDL apolipoprotein FCR and PR. These results disagree with the putative enhanced apo AI FCR in LPL deficient patients and suggest the need to reconsider the effects of LPL activity on HDL metabolism.

Abnormal HDL apolipoprotein A-I and A-II kinetics in hemodialysis patients: a stable isotope study.

Low levels of HDL cholesterol and its major apoprotein constituents apoA-I and apoA-II are common in patients who have ESRD and are undergoing hemodialysis (HD), but the metabolic basis for the low HDL is poorly understood. This study aimed to investigate in vivo metabolism of apoA-I and apoA-II in five normotriglyceridemic ESRD-HD patients and compared it with five control subjects using endogenous stable isotope labeling methods coupled with a multicompartmental modeling. HDL cholesterol, apoA-I, and apoA-II levels were markedly decreased in the ESRD-HD patients by 39, 30, and 44%, respectively, in comparison with the control subjects. Fractional catabolic rate of apoA-I was found to be significantly increased by 59% to 0.360 +/- 0.084/d in ESRD-HD patients as compared with control subjects of 0.227 +/- 0.076/d (P = 0.028), whereas the production rates remained unchanged. Conversely, the apoA-II production rate significantly decreased by 31% to 1.50 +/- 0.61 mg/kg per d in the ESRD-HD patients in comparison with control subjects of 2.17 +/- 0.40 mg/kg per d (P = 0.047) with apoA-II fractional catabolic rate unchanged. These results revealed that the decreased levels of apoA-I are due solely to the increased rate of catabolism, whereas the reduced apoA-II levels are due primarily to the decreased rate of production in ESRD-HD patients. This differential regulation of apoA-I and apoA-II further supports the concept that apoA-I and apoA-II have distinct metabolic pathways.

Albumin inhibits apolipoprotein AI and AII production in human hepatoblastoma cell line (Hep G2): additive effects of oleate–albumin complex

Although the role of multiple humoral agents (such as plasma albumin, glucose, hormones etc.) are implicated in lipoprotein metabolism, the mechanism of action of these agents on various steps of the synthesis and secretion of lipoproteins and apolipoproteins (protein moieties of lipoproteins) are not completely understood. Specifically, the hepatocellular mechanisms of the effect of albumin and fatty acids on apolipoprotein (apo) AI and AII [major proteins of high density lipoproteins (HDL)] synthesis and secretion are not known. Using human hepatoblastoma cells (Hep G2) as an in vitro model system, this study examined the effect of albumin and fatty acids on the synthesis, secretion, and the steady-state mRNA expression of apo AI and AII. The data indicated that the incubation of Hep G2 cells with albumin, dose-dependently, inhibited apo AI and AII accumulation (secretion) in the media, de novo synthesis, and the steady-state mRNA expression. Albumin did not alter total protein synthesis; thus the effect of albumin appeared to be specific for the synthesis and secretion of apo AI and apo AII. Free fatty acids (FFA) are transported by albumin and diseases characterized by enhanced FFA mobilization (e.g. diabetes mellitus) are associated with low HDL levels. Studies were therefore performed to examine the effect of albumin-bound-oleic acid on apo AI and apo AII production. The results showed that the albumin–oleate complex further increased the inhibitory effects of albumin on apo AI and apo AII production. These data suggest how HDL metabolism may be affected at the hepatocellular level by alterations in plasma albumin concentrations and/or fatty acid mobilization in clinical situations characterized by altered HDL levels.

In vivo evidence for increased apolipoprotein A-I catabolism in subjects with impaired glucose tolerance.

The in vivo kinetics of the HDL apolipoproteins (apo) A-I and A-II were studied in six subjects with impaired glucose tolerance (IGT) and six control subjects with normal glucose tolerance (NGT), using a stable isotope approach. During a 12-h primed constant infusion of L-[ring-13C6]-phenylalanine, tracer enrichment was determined in apoA-I and apoA-II from ultracentrifugally isolated HDL. The rates of HDL apoA-I and apoA-II production and catabolism were estimated using a one-compartment model-based analysis. Triglycerides were higher in IGT subjects (1.33 +/- 0.21 vs. 0.84 +/- 0.27 mmol/l, P < 0.05), but were within the normal range. HDL cholesterol and apoA-I levels were significantly lower in subjects with IGT (1.07 +/- 0.15 vs. 1.36 +/- 0.14 mmol/l, P < 0.05; 0.94 +/- 0.10 vs. 1.34 +/- 0.07 g/l, P < 0.01). In IGT subjects, HDL composition was significantly altered, characterized by an increase in HDL triglycerides (4.9 +/- 1.9 vs. 3.2 +/- 1.0%, P < 0.05) and HDL phospholipids (34.7 +/- 2.6 vs. 27.5 +/- 5.8%, P < 0.05) and a decrease in HDL cholesteryl esters (10.1 +/- 2.0 vs. 12.7 +/- 2.9%, P < 0.05) and HDL apoA-I (31.5 +/- 4.4 vs. 43.2 +/- 2.4%, P < 0.05). The mean fractional catabolic rate (FCR) of HDL apoA-I was significantly higher in IGT subjects (0.34 +/- 0.05 vs. 0.26 +/- 0.03 day(-1), P < 0.01), while the HDL apoA-I production rate (PR), as well as the PR and FCR of HDL apoA-II, showed no differences between the two groups. There were significant correlations between HDL apoA-I FCR and the following parameters: HDL apoA-I (r = -0.902, P < 0.001), HDL cholesterol (r = -0.797, P = 0.001), plasma triglycerides (r = 0.743, P < 0.01), HDL triglycerides (r = 0.696, P < 0.01), and cholesterol ester transfer protein activity (r = 0.646, P < 0.01). We observed a strong positive association between increased apoA-I catabolism and insulin (r = 0.765, P < 0.01) and proinsulin (r = 0.797, P < 0.01) concentrations. These data support the hypothesis that the decrease in HDL cholesterol and apoA-I levels in IGT is principally the result of an enhanced apoA-I catabolism. The latter seems to be an early metabolic finding in IGT even when other lipid parameters, especially plasma triglycerides, still appear to be not or only weakly affected.

Fish-eye disease: Structural and in vivo metabolic abnormalities of high-density lipoproteins

Fish-eye disease (FED) in humans is characterized by corneal opacities and markedly decreased plasma concentrations of high-density lipoprotein (HDL) cholesterol, apolipoprotein (apo) AI, and apo AII, but no tendency to precocious atherosclerosis is present. To elucidate this paradox, the structure of HDL, the potential of serum to promote cholesterol efflux from cultured cells, and the in vivo metabolism of HDL were examined in a 53-year-old woman with a FED syndrome in association with a markedly decreased lecithin:cholesterol acyltransferase (LCAT) activity in HDL due to a mutation of the LCAT gene (Arg 158 → Cys). HDLs isolated by ultracentrifugation were small and enriched in unesterified cholesterol and phospholipids at the expense of cholesteryl esters and proteins. The apolipoprotein content showed an enrichment in apo E and apo AIV, whereas apo AI and apo AII were dramatically reduced. Sodium dodecyl sulfate—polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting using specific antibodies showed that the apo E was free or covalently bound to apo AII. These particles analyzed by electron microscopy were small and round lipoproteins with a size similar to the smallest fraction of normal HDL 3. The potential capacity of the serum to promote efflux from the cells was approximately 40% of control serum levels, but FED HDLs were as efficient as control HDLs in promoting cholesterol efflux from cells. To assess the metabolism of HDL apolipoproteins, in vivo apolipoprotein kinetic studies were performed using endogenous labeling techniques in the patient with FED and three control subjects. All subjects were administered D 3-labeled leucine by primed constant infusion for up to 10 hours. The fractional synthetic rates (FSRs) of apo AI and apo AII in the patient were 0.674 and 0.594 per day, clearly higher than in controls, 0.210 ± 0.053 and 0.148 ± 0.014 per day for apo AI and apo AII, respectively. Apo AI and apo AII production rates in the patient with FED were normal, 11.32 and 2.62 mg/kg · d, respectively, as compared with those in normal subjects, 11.45 ± 1.23 and 2.68 ± 0.17 mg/kg · d. These data established that hypoalphalipoproteinemia in FED was caused by marked hypercatabolism of apo AI and apo AII. This hypercatabolism could be the consequence of structural abnormalities due to the selective LCAT deficiency. In conclusion, two steps of reverse cholesterol transport, cholesterol efflux and apo-HDL metabolism, appeared particularly efficient. This efficiency could participate in the absence of premature atherosclerosis in FED patients as regards the low HDL level.

Apolipoprotein A-II production rate is a major factor regulating the distribution of apolipoprotein A-I among HDL subclasses LpA-I and LpA-I:A-II in normolipidemic humans.

HDLs are heterogeneous in their apolipoprotein composition. Apolipoprotein (apo) A-I and apoA-II are the major proteins found in HDL and form the two major HDL subclasses: those that contain only apoA-I (LpA-I) and those that contain both apoA-I and apoA-II (LpA-I:A-II). Substantial evidence indicates that these two subclasses differ in their in vivo metabolism and effect on atherosclerosis, with LpA-I the more specifically protective subfraction against atherosclerosis. The purpose of this study was to investigate the effect of apoA-I and apoA-II production and catabolism on plasma LpA-I and LpA-I:A-II levels. Fifty normolipidemic subjects (those with HDL cholesterol levels in the top and bottom tenth percentiles were excluded) underwent kinetic studies with radiolabeled apoA-I and apoA-II, and the kinetic parameters of apoA-I and apoA-II were correlated with LpA-I and LpA-I:A-II levels. ApoA-I levels were strongly correlated with apoA-I residence times and less strongly correlated with apoA-I production rates. In contrast, apoA-II levels were correlated only with apoA-II production rates and not with apoA-II residence times. Levels of apoA-I in LpA-I were correlated with apoA-I residence times, whereas levels of apoA-I in LpA-I:A-II were correlated primarily with apoA-II production rates. The fraction of apoA-I in LpA-I was highly inversely correlated with apoA-II production rate (r = -.67, P < .001). In multiple regression analysis, apoA-II production rate was the most significant independent variable determining percent apoA-I in LpA-I among all the kinetic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)