Effects of lipid-lowering drugs on reverse cholesterol transport gene expressions in peripheral blood mononuclear and HepG2 cells.
OBJECTIVE
The ATP-binding cassette transporters, ABCA1 and ABCG1, are LXR-target genes that play an important role in reverse cholesterol transport. We examined the effects of inhibitors of the cholesterol absorption (ezetimibe) and synthesis (statins) on expression of these transporters in HepG2 cells and peripheral blood mononuclear cells (PBMCs) of individuals with primary (and nonfamilial) hypercholesterolemia (HC).


METHODS
A total of 48 HC individuals were treated with atorvastatin (10 mg/day/4 weeks) and 23 were treated with ezetimibe (10 mg/day/4 weeks), followed by simvastatin (10 mg/day/8 weeks) and simvastatin plus ezetimibe (10 mg of each/day/4 weeks). Gene expression was examined in statin- or ezetimibe-treated and control HepG2 cells as well as PBMCs using real-time PCR.


RESULTS
In PBMCs, statins and ezetimibe downregulated ABCA1 and ABCG1 mRNA expression but did not modulate NR1H2 (LXR-β) and NR1H3 (LXR-α) levels. Positive correlations of ABCA1 with ABCG1 and of NR1H2 with NR1H3 expressions were found in all phases of the treatments. In HepG2 cells, ABCA1 mRNA levels remained unaltered while ABCG1 expression was increased by statin (1.0-10.0 µM) or ezetimibe (5.0 µM) treatments. Atorvastatin upregulated NR1H2 and NR1H3 only at 10.0 µM, meanwhile ezetimibe (1.0-5.0 µM) downregulated NR1H2 but did not change NR1H3 expression.


CONCLUSIONS
Our findings reveal that lipid-lowering drugs downregulate ABCA1 and ABCG1 mRNA expression in PBMCs of HC individuals and exhibit differential effects on HepG2 cells. Moreover, they indicate that the ABCA1 and ABCG1 transcript levels were not correlated directly to LXR mRNA expression in both cell models treated with lipid-lowering drugs.
Genvigir
Fabiana Dalla Vecchia
FD
Department of Clinical & Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil. fabidalla@usp.br
Rodrigues
Alice Cristina
AC
Cerda
Alvaro
A
Arazi
Simone Sorkin
SS
Willrich
Maria Alice Vieira
MA
Oliveira
Raquel
R
Hirata
Mario Hiroyuki
MH
Dorea
Egidio Lima
EL
Bernik
Márcia Martins
MM
Curi
Rui
R
Hirata
Rosario Dominguez Crespo
RD
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000042:Absorption / Q000187:drug effects; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D001384:Azetidines / Q000494:pharmacology; D001692:Biological Transport / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D001384:Azetidines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D057093:Orphan Nuclear Receptors; D011758:Pyrroles; D012333:RNA, Messenger; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; D000069438:Ezetimibe