Effects of lipid-lowering drugs on reverse cholesterol transport gene expressions in peripheral blood mononuclear and HepG2 cells

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Genvigir, Fabiana Dalla Veccfhia ^[1] ; Rodrigues, Alice Cristina ^[1] ; Cerda, Alvaro ^[1] ; Arazi, Simone Sorkin ^[1] ; Vieira Willrich, Maria Alice ^[1] ; Oliveira, Raquel ^[1] ; Hirata, Mario Hiroyuki ^[1] ; Dorea, Egidio Lima ^[2] ; Bernik, Marcia Martins ^[2] ; Curi, Rui ^[3] ; Hirata, Rosario Dominguez Crespo ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Clin & Toxicol Anal, Sch Pharmaceut Sci, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Univ Hosp, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PHARMACOGENOMICS; v. 11, n. 9, p. 1235-1246, SEP 2010.
• Citações Web of Science: 16

Resumo

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-beta) and NR1H3 (LXR-alpha) 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 mu M) or ezetimibe (5.0 mu M) treatments. Atorvastatin upregulated NR1H2 and NR1H3 only at 10.0 mu M, meanwhile ezetimibe (1.0-5.0 mu M) 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. (AU)

• Processo FAPESP: 06/06196-0 - Estudo farmacogenômico: efeitos de hipolipemiantes sobre a expressão gênica de fatores de transcrição envolvidos na regulação do colesterol
• Beneficiário: Rosario Dominguez Crespo Hirata
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/15125-8 - Influência de inibidores de síntese e absorção de colesterol na expressão de proteínas do transporte reverso do colesterol em células HepG2 e CACO-2
• Beneficiário: Rosario Dominguez Crespo Hirata
• Modalidade de apoio: Auxílio à Pesquisa - Regular