Abstract 15463: Pioglitazone Enhances Cholesterol Efflux From Macrophages by Increasing ABCA1/ABCG1 Expressions via LXRα/PPARγ Pathway: Findings From in vitro and ex vivo Studies
A peroxisome proliferator-activated receptor γ (PPARγ) agonist, pioglitazone (Pio) reduced cardiovascular events in type 2 diabetic patients. ABCA1, which is involved in apolipoprotein A-I (apoA-I)-mediated cholesterol efflux from macrophages (MΦ), is regulated by PPARγ-liver receptor X (LXR) pathway. ABCG1 level is reportedly induced by Pio; however, the mechanisms for PPARγ-mediated ABCG1 expression have not been fully characterized. We therefore investigated how PPARγ regulated ABCG1 expression, and whether Pio enhanced cholesterol efflux ex vivo. The Results revealed that Pio increased ABCA1/G1 expressions, resulting in enhanced cholesterol efflux from MΦ. Promoter assays using reporter constructs containing human ABCG1 promoter A and B, with or without mutated LXR-binding sites revealed that Pio activated both promoters in an LXR-dependent manner. Next, knockdown experiments using microRNA for PPARγ or LXRα revealed that Pio-induced upregulation of ABCG1 major transcripts driven by promoter B were completely abolished by the former, while partially by the latter. In contrast, the stimulatory effects of Pio on ABCA1 were abolished by knockdown of either PPARγ or LXRα. Finally, to further investigate whether these observations can translate into human circumstances, Pio (30 mg) or placebo was administered, in a cross-over design, to 14 type 2 diabetic patients and sera were obtained before (pre) and 2 hr (post) after the administration As shown in Figure, MΦ treated with post-Pio sera, compared to pre-Pio, showed a significant enhancement of apoA-I- and HDL-mediated cholesterol efflux by increasing ABCA1/G1. In Conclusions, in addition to the effect on ABCA1, Pio enhanced cholesterol efflux form MΦ in vitro and ex vivo by increasing ABCG1, which was regulated in LXR-dependent and -independent manners. Cardioprotective properties of Pio might therefore be associated, at least in part, with an enhanced anti-atherogenic function of HDL.
- © 2010 by American Heart Association, Inc.