Plasma cholesterol is hyperresponsive to statin in ABCG5/ABCG8 transgenic mice.
Interindividual variation exists in response to statin therapy. It has been hypothesized that subjects with higher baseline cholesterol synthesis rates are more sensitive to statins. To directly test this hypothesis, mice overexpressing the heterodimeric ATP-binding cassette (ABC) transporter G5/G8 (G5G8(Tg) mice) were treated with lovastatin because they have a compensatory increase in cholesterol biosynthesis as a result of increased cholesterol excretion into bile and feces. As expected, lovastatin treatment did not alter plasma and hepatic cholesterol levels in wild-type mice. Interestingly, this treatment significantly reduced plasma concentration and hepatic content of cholesterol by 42% and 17.3%, respectively, in the statin-treated versus untreated G5G8(Tg) mice despite a greater feedback upregulation of genes in the pathway of cholesterol biosynthesis in the lovastatin-treated G5G8(Tg) mice. The reduced plasma cholesterol concentration is unlikely to be attributed to LDL and HDL receptors because the protein levels of both receptors remained unchanged. Surprisingly, statin treatment resulted in an increase in biliary cholesterol concentration, which was associated with an upregulation in hepatic mRNA and protein levels of ABCG5 and ABCG8, and in hepatic mRNA levels of Niemann-Pick C1-Like 1 (NPC1L1), a gene that is required for intestinal cholesterol absorption. In conclusion, mice with higher endogenous cholesterol synthesis rates are more sensitive to statin. A synergistic hypocholesterolemic effect could be potentially achieved in humans by simultaneously inhibiting cholesterol biosynthesis and promoting ABCG5/ABCG8-mediated cholesterol excretion.
Tang
Weiqing
W
Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Ma
Yinyan
Y
Yu
Liqing
L
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D050556:Fatty Acid-Binding Proteins; D005260:Female; D005704:Gallbladder / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D026502:LDL-Receptor Related Proteins; D008074:Lipoproteins / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008148:Lovastatin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000187:drug effects; D011973:Receptors, LDL / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D050556:Fatty Acid-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D026502:LDL-Receptor Related Proteins; D008074:Lipoproteins; C116415:Lrp4 protein, mouse; D012333:RNA, Messenger; D011973:Receptors, LDL; D002784:Cholesterol; D008148:Lovastatin