Effects of different doses of atorvastatin on human apolipoprotein B-100, B-48, and A-I metabolism

Abstract

Nine hypercholesterolemic and hypertriglyceridemic subjects were enrolled in a randomized, placebocontrolled, double-blind, crossover study to test the effect of atorvastatin 20 mg/day and 80 mg/day on the kinetics of apolipoprotein B-100 (apoB-100) in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in TRL, and of apoA-I in HDL. Compared with placebo, atorvastatin 20 mg/day was associated with significant reductions in TRL, IDL, and LDL apoB-100 pool size as a result of significant increases in fractional catabolic rate (FCR) without changes in production rate (PR). Compared with the 20 mg/day dose, atorvastatin 80 mg/day caused a further significant reduction in the LDL apoB-100 pool size as a result of a further increase in FCR. ApoB-48 pool size was reduced significantly by both atorvastatin doses, and this reduction was associated with nonsignificant increases in FCR. The lathosterol-campesterol ratio was decreased by atorvastatin treatment, and changes in this ratio were inversely correlated with changes in TRL apoB-100 and apoB-48 PR. No significant effect on apoA-I kinetics was observed at either dose of atorvastatin. Our data indicate that atorvastatin reduces apoB-100-and apoB-48-containing lipoproteins by increasing their catabolism and has a dose-dependent effect on LDL apoB-100 kinetics. Atorvastatin-mediated changes in cholesterol homeostasis may contribute to apoB PR regulation.-Lamon-Fava, S.,

Effects of CETP inhibition on triglyceride-rich lipoprotein composition and apoB-48 metabolism

“…Moreover, atorvastatin therapy in hyperlipidemic men has been shown to stimulate intestinal mRNA expression of the LDL receptor and Niemann-Pick C1Like 1 and to decrease mRNA levels dysbetalipoproteinemia ( 38,39 ), and CHD ( 40,41 ). The reductions have been associated with enhanced clearance of apoB-48 ( 22 ) and chylomicron-like emulsions ( 42 ) in subjects with dyslipidemia. In subjects with diabetes, Hogue et al (43) found that atorvastatin reduced TRL apoB-48 concentrations primarily by decreasing its production.…”

“…Relative to placebo, torcetrapib decreased plasma TG levels by 21 ± 8% ( P = 0.04) in the once daily cohort, by 7 ± 8% ( P not signifi cant) in the The SAAM II program (University of Washington, Seattle, WA) was used to determine the fractional catabolic rate (FCR) of apoB-48 using a previously described multicompartmental model ( 22,24 ). The model assumed a constant enrichment of the precursor pool, as has been demonstrated in metabolic studies using a primed-constant infusion to administer labeled leucine ( 22,24,25 ). Determination of the FCR is independent of the level of precursor enrichment.…”

“…As described previously ( 22 ), TRL proteins were separated by gradient SDS-PAGE and transferred to a Westran S polyvinylidene difl uoride membrane (GE Life Sciences, Piscataway, NJ) using a Tris-glycine-methanol system. ApoB-48 bands were visualized by Coomassie blue R-250, excised from the membrane, and hydrolyzed with 12 N HCl at 110°C for 24 h. Amino acids were converted to n-propyl ester and heptafl uorobutyramide derivatives and analyzed for isotopic enrichment by electron capture negative chemical ionization gas chromatography-mass spectrometry.…”

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

“…Large ␣-1 particles increase with weight loss, niacin, certain statins (atorvastatin, rosuvastatin), and CETP inhibitors (52)(53)(54)(55)(56)(57). Increasing the concentrations of apo AI in ␣-1 HDL to Ͼ200 mg/L (0.52 mmol/L) with a simvastatin/niacin combination has been associated with lack of progression and in some individuals with regression of coronary atherosclerosis (51 ).…”

Overview of the LDL receptor: relevance to cholesterol metabolism and future approaches for the treatment of coronary heart disease

“…6 However, most cases of hypercholesterolemia seen in the general population are likely due to reduced LDL uptake from plasma either resulting from reduced LDLR activity or to 34 Effective pharmacologic treatment with statins results in enhanced LDL clearance from plasma. 35 The next section will describe the molecular mechanisms responsible for these changes that lead to lower LDL levels ( Figure 3). …”