Statins as effectors of key activities involved in apoE-dependent VLDL metabolism: review and hypothesis.

ABSTRACT

Statins influence the major reactions of TG and HDL metabolism controlled, in part, by apoE level and its isoforms on the transcriptional, translational and post-translational levels. The existing unexplained maximal and minimal lipid responses (lowering TG and rising HDL-C) for varepsilon2 and varepsilon4 APOE alleles, respectively, following statin therapy may be completely described by the minimal set of the effects that follow (i) the lowest and the highest efficiency of the binding of apoE2 and apoE4, respectively, to the LDL receptor; (ii) the increased competition of apoE4-containing VLDL with LDL for the LDL receptor; (iii) the isoform-independent induction by statin of the LDL receptor expression; (iv) the highest inhibition of hepatic lipase and the highest activation of lipoprotein lipase-directed lipolytic pathways for varepsilon2-bearing patients by statins; and (v) the increased clearance of large apoE-containing HDL, specifically with apoE4, at highest statin doses. These effects may be modulated additionally by apoE-controlled TG secretion. The molecular targets demonstrating an isoform-dependent sensitivity to statin therapy are outlined.