Statins downregulate ATP-binding-cassette transporter A1 gene expression in macrophages

Sone, Hirohito; Shimano, Hitoshi; Miao, Shuying; Nakakuki, Masanori; Takahashi, Akimitsu; Sakai, Masakazu; Sakamoto, Yuichiro; Yokoo, Tomotaka; Matsuzaka, Ken; Okazaki, Hiroaki; Nakagawa, Yoshimi; Iida, Kaoruko; Suzuki, Hiroaki; Toyoshima, Hideo; Horiuchi, Seikoh; Yamada, Nobuhiro

doi:10.1016/j.bbrc.2004.02.121

Cited by 57 publications

(41 citation statements)

References 30 publications

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“…For ABCA1, different concentrations of atorvastatin, simvastatin or ezetimibe did not alter the gene transcription. On the contrary, treatment of Fu5AH rat hepatoma or HepG2 cells with statins increased the transpcript levels or improved ABCA1-mediated lipid efflux [15,18,40]. Consistent with our results, hepatic Abca1 levels of mice fed with basal diet was not affected by ezetimibe treatment [38].…”

Section: Pharmacogenomics (2010) 11(9)supporting

confidence: 90%

“…Other authors also reported the downregulatory effect on ABCA1 and ABCG1 transcription in human and murine macrophages treated in vitro with different statins [11][12][13][14][15]. Furthermore, statins also reduced the ABCA1 protein and cholesterol efflux mediated in these cells [11,12,14].…”

Section: Pharmacogenomics (2010) 11(9)mentioning

confidence: 98%

“…Until now, in vitro effects of statins on ABCA1 and ABCG1 expression have been more established in monocytes and macrophages [11][12][13][14][15][16]. Conversely, there are few and conflicting studies describing the effects of statins on these genes in hepatic cells or in vivo approaches.…”

Section: Effects Of Lipid-lowering Drugs On Reverse Cholesterol Transmentioning

confidence: 99%

“…Moreover, we examined whether ABCA1 and ABCG1 expression in statin-or ezetimibe-treated human hepatocellular carcinoma (HepG2) cells differs from the expression in PBMCs. Although the ABCA1 levels were already evaluated in HepG2 cells treated with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, conflicting results were reported by other studies [13,15,18].…”

Section: Effects Of Lipid-lowering Drugs On Reverse Cholesterol Transmentioning

confidence: 99%

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

et al. 2010

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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

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Section: Pharmacogenomics (2010) 11(9)supporting

confidence: 90%

Section: Pharmacogenomics (2010) 11(9)mentioning

confidence: 98%

Section: Effects Of Lipid-lowering Drugs On Reverse Cholesterol Transmentioning

confidence: 99%

Section: Effects Of Lipid-lowering Drugs On Reverse Cholesterol Transmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2010

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“…Hepatic ABCA1 expression is regulated by a dual promoter system driven by SREBP2 and liver X receptor (LXR), and this system is liver-specific (19). Statins increased ABCA1 mRNA levels in hepatoma cell lines, although ABCA1 mRNA levels were reduced in macrophage or fibroblast cell lines (16,17,20). Here, we investigated the mechanism of hepatic ABCA1 regulation by statins using the rat hepatoma cell line McARH7777 cells.…”

Section: Introductionmentioning

confidence: 99%

Pitavastatin Increases ABCA1 Expression by Dual Mechanisms: SREBP2-Driven Transcriptional Activation and PPARα-Dependent Protein Stabilization but Without Activating LXR in Rat Hepatoma McARH7777 Cells

et al. 2011

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Abstract. Hepatic ATP-binding cassette transporter A1 (ABCA1) plays a key role in high-density lipoprotein (HDL) production by apolipoprotein A-I (ApoA-I) lipidation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, increase ABCA1 mRNA levels in hepatoma cell lines, but their mechanism of action is not yet clear. We investigated how statins increase ABCA1 in rat hepatoma McARH7777 cells. Pitavastatin, atorvastatin, and simvastatin increased total ABCA1 mRNA levels, whereas pravastatin had no effect. Pitavastatin also increased ABCA1 protein. Hepatic ABCA1 expression in rats is regulated by both liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP2) pathways. Pitavastatin repressed peripheral type ABCA1 mRNA levels and its LXR-driven promoter, but activated the liver-type SREBPdriven promoter, and eventually increased total ABCA1 mRNA expression. Furthermore, pitavastatin increased peroxisome proliferator-activated receptor α (PPARα) and its downstream gene expression. Knockdown of PPARα attenuated the increase in ABCA1 protein, indicating that pitavastatin increased ABCA1 protein via PPARα activation, although it repressed LXR activation. Furthermore, the degradation of ABCA1 protein was retarded in pitavastatin-treated cells. These data suggest that pitavastatin increases ABCA1 protein expression by dual mechanisms: SREBP2-mediated mRNA transcription and PPARα-mediated ABCA1 protein stabilization, but not by the PPAR-LXR-ABCA1 pathway.

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ABCA1, from pathology to membrane function

Zarubica

Trompier

Chimini

2006

Pflugers Arch - Eur J Physiol

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The ABCA1 transporter is the prototype of the A class of mammalian adenosine triphosphate binding cassette transporters and one of the largest members of this family. ABCA1 has been originally identified as an engulfment receptor on macrophages and, more recently, it has been shown to play an essential role in the handling of cellular lipids. Indeed by promoting the effluxes of membrane phospholipids and cholesterol to lipid-poor apoprotein acceptors, ABCA1 controls the formation of high-density lipoproteins and thus the whole process of reverse cholesterol transport. A number of additional phenotypes have been found in the mouse model of invalidation of the ABCA1 gene. In spite of their clinical diversity, they all are extremely sensitive to variations in the physicochemical properties of the cell membrane, which ABCA1 controls as a lipid translocator.

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Statins downregulate ATP-binding-cassette transporter A1 gene expression in macrophages

Cited by 57 publications

References 30 publications

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

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

Pitavastatin Increases ABCA1 Expression by Dual Mechanisms: SREBP2-Driven Transcriptional Activation and PPARα-Dependent Protein Stabilization but Without Activating LXR in Rat Hepatoma McARH7777 Cells

ABCA1, from pathology to membrane function

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