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

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 ɛ2 and ɛ4 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 ɛ2-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.