Influence of Atorvastatin on Apolipoprotein E and AI Kinetics in Patients with Type 2 Diabetes

Abstract

Atorvastatin reduces both plasma cholesterol and triglyceride concentrations in patients with type 2 diabetes, but mechanisms underlying triglyceride decrease and the effect of atorvastatin on high density lipoprotein (HDL) still remain unclear. Apolipoprotein (apo) E plays a crucial role in modulating production and clearance of triglyceride-rich very low density lipoprotein (VLDL). The main effect of apoAI is to modulate HDL metabolism. The aim of this work was to study the influence of atorvastatin on apoAI and apoE kinetics and to determine whether its hypocholesterolemic and hypotriglyceridemic effects could be related to changes in this apolipoprotein metabolism. Plasma VLDL-apoE, HDL-apoE, and HDL-apoAI were studied in seven patients with diabetes with mixed hyperlipidemia using a stable isotope labeling technique ([ 2 H 3 ]leucineprimed constant infusion) and monocompartmental model before and after 2 months of treatment with 40 mg/day of atorvastatin. Plasma apoE concentration was significantly reduced (44.1 Ϯ 19.1 versus 32 Ϯ 11.6 mg/l, p Ͻ 0.05) after treatment. This decrease was associated with a diminution of HDL-apoE concentration (17.46 Ϯ 6.71 versus 13.37 Ϯ 6.05 mg/l, p Ͻ 0.05) and production rate (0.202 Ϯ 0.085 versus 0.119 Ϯ 0.047 mg/kg/day, p Ͻ 0.05), whereas an increase in VLDL-apoE concentration (6.44 Ϯ 2.16 before versus 9.23 Ϯ 4.02 mg/l after, p Ͻ 0.05) and production rate (0.827 Ϯ 0.367 versus 1.524 Ϯ 0.664 mg/kg/day, p Ͻ 0.05) was observed. No significant difference was observed after treatment for apoAI parameters. We conclude that atorvastatin treatment promotes different apoE distribution between HDL and VLDL, favoring VLDL apoE content. The increased number of apoE per VLDL particle suggests that atorvastatin could enhance the direct catabolism of triglyceride-rich VLDL through apoE receptor pathways.

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

“…In our study, no significant effect of atorvastatin on apoA-I PR or FCR was observed. These results are in agreement with previously published studies indicating no effect of atorvastatin on the kinetics of apoA-I (6,(40)(41)(42)(43). The change in HDL-C with atorvastatin was independent of apoA-I kinetics.…”

Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome

“…Higher VLDL apoE concentration and PR were associated with elevated plasma and VLDL triglycerides ( 25,27 ). Our subjects exhibited overproduction of VLDL apoE, with concentrations of plasma and VLDL apoE within range of those previously reported in hypertriglyceridemic subjects ( 20,21,25,27 ). It is, however, important to acknowledge that, in this study, VLDL apoE PR represents the transport of apoE through the VLDL pool.…”

“…The kinetics of HDL apoE were not examined in our subjects. Previous studies suggest that atorvastatin altered apoE distribution between VLDL and HDL in type 2 diabetic subjects ( 20 ). Therefore, the reported increase in VLDL apoE FCR with fenofi brate and atorvastatin may represent increased removal of VLDL apoE into tissues or organs, with or without the whole VLDL particle, or a greater fraction of VLDL apoE that is transported to HDL per unit time.…”

“…The triglyceride-lowering effect of statins may also be partly due to altered apoE concentration and metabolism. To date, two studies have examined the effect of statins on VLDL apoE kinetics ( 20,21 ), but the fi ndings were inconsistent.…”

“…Cohn et al reported that atorvastatin 40 mg/day decreased VLDL apoE concentration by decreasing VLDL apoE PR in six subjects with combined hyperlipidemia ( 21 ). By contrast, BachNgohou showed, in an uncontrolled study, that atorvastatin 40 mg/day increased VLDL apoE concentration and PR in seven dyslipidemic diabetic subjects ( 20 ). Discrepancies among these studies may relate to different clinical and biochemical characteristics of study subjects, as well as study design.…”