Effects of Pravastatin on the Expression of ATP-Binding Cassette Transporter A1

Abstract

In vitro inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase causes the suppression of liver X receptor (LXR) activity. Because LXR regulates the expression of ATP-binding cassette transporter (ABC) A1, which is involved in the high-density lipoprotein-related reverse cholesterol transport pathway, we examined the effects of an HMG-CoA reductase inhibitor pravastatin on ABCA1 expression in vitro and in vivo. Pravastatin (10 M) significantly reduced the transcript levels of murine ABCA1 gene by 35% in RAW264.7 macrophages under a lipoprotein-deficient condition. The inhibition was due to the decreased mevalonic acid production because addition of exogenous mevalonic acid restored ABCA1 mRNA levels. In addition, cholesterol and 22(R)-hydroxycholesterol thoroughly blunted the inhibition. Furthermore, pravastatin did not decrease ABCA1 mRNA and protein levels in HepG2 hepatocytes even in the absence of exogenous LXR agonists. Oral dosing of pravastatin (0.1% concentration in drinking water) for 24 h or 2 weeks to mice did not decrease ABCA1 mRNA and protein levels in the liver and leukocytes. Interestingly, pravastatin significantly increased both hepatic and leukocyte LXR␣ mRNA levels. Thus, although HMG-CoA reductase inhibitors suppress ABCA1 mRNA expression in the absence of LXR agonists, in vivo inhibition of HMG-CoA reductase is unlikely to cause such suppression.

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

“…On the contrary, pravastatin did not change the mRNA expression and protein ABCA1 in leukocytes of mice [13] and simvastatin increased ABCA1 levels in PBMCs of Type II diabetes patients in vivo [35]. However, differences between human and mice cholesterol metabolism and the absence of diabetic patients in our study may explain the different findings.…”

“…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].…”

“…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].…”

“…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.…”

Profile of rhythmic gene expression in the livers of obese diabetic KK-Ay mice

“…The real-time quantitative PCR was performed with the ABI Prism 7700 sequence detection system (Applied Biosystems, Foster City, CA), as previously described [14,19]. All specific primer sets and TaqMan probes were obtained from Applied Biosystems, and their…”