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

Abstract

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.

Serum CETP status is independently associated with reduction rates in LDL-C in pitavastatin-treated diabetic patients and possible involvement of LXR in its association

“…Atorvastatin, a strong statin, was shown to decrease the expression of LXR-α in macrophages [ 24 ]. Pitavastatin repressed LXR activation in a rat hepatoma cell line [ 25 ], which was indirectly supported by our result in which the activation of LXR by T0901317 antagonized the pitavastatin-induced reduction in CETP levels in HepG2 cells (Fig. 1 ).…”

Pleiotropic effects of pitavastatin

“…It has been proposed that statins increase HDL-C by inhibiting cholesteryl ester transfer protein and stimulating ApoAI synthesis [81], potentially via a mechanism mediated by RhoA suppression [82, 83]. There is also evidence that pitavastatin may increase HDL-C by increasing expression of ApoAI and ATP-binding cassette transporter A1, key components of reverse cholesterol transport [84–86]. …”

“…It has been proposed that statins increase HDL-C by inhibiting cholesteryl ester transfer protein and stimulating ApoAI synthesis [81], potentially via a mechanism mediated by RhoA suppression [82, ]. There is also evidence that pitavastatin may increase HDL-C by increasing expression of ApoAI and ATP-binding cassette transporter A1, key components of reverse cholesterol transport [84][85][86]. Studies of the effects of statins on dysfunctional HDL species would be of interest because, currently, only niacin [76] and vitamin E in patients with diabetes with the haptoglobulin 2-2 genotype [87] are known to have beneficial effects on HDL dysfunction.…”

Importance of Assessing the Effect of Statins on the Function of High- Density Lipoproteins on Coronary Plaque

“…Several reports demonstrated that ApoA-I mimetics enhance B cholesterol efflux and regression of atherosclerotic lesions [22,23]. Pitavastatin also increases hepatic ATP-binding cassette transporter A1 (ABCA1) expression, which plays a key molecule for cholesterol efflux from the hepatoma cell, through sterol regulation element-binding protein-2 (SREBP2) and Rho-PPARα pathways [24]. The other pathway to increase ApoA-I and ABCA1 expression is adiponectin.…”