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 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.
Dergunov
Alexander D
AD
National Research Centre for Preventive Medicine, 10, Petroverigsky street, 101990 Moscow, Russia. dergunov@img.ras.ru
Visvikis-Siest
Sophie
S
Siest
Gerard
G
D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011973:Receptors, LDL / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D001057:Apolipoproteins E; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D014280:Triglycerides; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008049:Lipase; D008071:Lipoprotein Lipase