Effects of Lipid-Lowering Drugs on Reverse Cholesterol Transport Gene Expressions in Peripheral Blood Mononuclear and Hepg2 Cells

Abstract

Aims: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). Materials & 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-b) and NR1H3 (LXR-a) 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. Conclusion: 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.KEYWORDS: ABCA1 n ABCG1 n ezetimibe n mRNA expression n PBMC n statins

Statin-Induced Decrease in ATP-Binding Cassette Transporter A1 Expression via microRNA33 Induction may Counteract Cholesterol Efflux to High-Density Lipoprotein

“…Our data are also consistent with previous findings that short-term treatment with low-dose atorvastatin decreased ABCA1 and ABCG1 mRNA expression in blood cells of hypercholesterolemic patients [23]. In addition, more recent studies using HDL as the lipid acceptor to evaluate ABCG1-mediated cholesterol efflux have shown that simvastatin and atorvastatin reduce cholesterol efflux in human macrophages.…”

Atorvastatin and hormone therapy effects on APOE mRNA expression in hypercholesterolemic postmenopausal women

“…Blood was diluted in phosphate buffered saline (1:1) and this suspension was layered in Hystopaque-1077 (Sigma-Aldrich, MO, USA) and centrifuged for 30 min at 400 × g at room temperature. PBMC were collected from the interphase and immediately used for RNA extraction [16].…”

ABCA1 and ABCG1 expressions are regulated by statins and ezetimibe in Caco-2 cells

“…We have previously shown that lipid-lowering drugs can infl uence the expression of two important genes involved in the HDL metabolism, ABCA1 and ABCG1 , in a cell-specifi c manner (5) . According to our fi ndings, atorvastatin, simvastatin or ezetimibe treatment downregulated ABCA1 and ABCG1 mRNA expression in peripheral blood mononuclear cells of hypercholesterolemic individuals, even in the absence of changes in serum HDL-C or apolipoprotein AI (apoAI), the major protein of HDL.…”