Pioglitazone enhances cholesterol efflux from macrophages by increasing ABCA1/ABCG1 expressions via PPARγ/LXRα pathway: Findings from in vitro and ex vivo studies
| Autor: | Makoto Ayaori, Seibu Mochizuki, Hideki Ozasa, Masatsune Ogura, Shunichi Takiguchi, Michihiro Yoshimura, Makoto Sasaki, Shunpei Horii, Yoshio Terao, Tomohiro Komatsu, Yoshinari Uehara, Harumi Uto-Kondo, Tetsuya Hisada, Kazuhiro Nakaya, Maki Iizuka, Katsunori Ikewaki, Emi Yakushiji |
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| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Oxysterol Transactivation Internal medicine polycyclic compounds medicine Humans Hypoglycemic Agents Liver X receptor Receptor Cells Cultured ATP Binding Cassette Transporter Subfamily G Member 1 Liver X Receptors Pioglitazone biology Macrophages Orphan Nuclear Receptors PPAR gamma Cholesterol HEK293 Cells Endocrinology Diabetes Mellitus Type 2 ABCG1 ABCA1 biology.protein ATP-Binding Cassette Transporters RNA Interference Thiazolidinediones lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine Ex vivo ATP Binding Cassette Transporter 1 medicine.drug |
| Zdroj: | Atherosclerosis. 219:141-150 |
| ISSN: | 0021-9150 |
| DOI: | 10.1016/j.atherosclerosis.2011.07.113 |
| Popis: | Objective Pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, reportedly reduces cardiovascular events in diabetic patients. ATP cassette binding transporters (ABC) A1 and G1 are pivotal molecules for cholesterol efflux (ChE) from macrophages and high density-lipoprotein biogenesis, and the A1 transporter is regulated by a PPARγ-liver receptor X (LXR) pathway. Also, pioglitazone induces ABCG1 expression, though the exact mechanism remains unclear. We therefore investigated the effects of pioglitazone on ABCA1/G1 expression in vitro and ex vivo. Methods The effects of pioglitazone on ChE and ABCA1/G1 expressions in macrophages were assessed. Then, mRNA was quantified in macrophages when PPARγ/LXR inhibition by siRNA or overexpression of oxysterol sulfotransferase was performed. ABCA1/G1 promoter activity with mutated LXR-responsive elements was also measured. As an ex vivo study, 15 type 2 diabetic patients were administered pioglitazone or placebo, and ChE assays and protein expressions were determined using macrophages cultured with the corresponding sera. Results Pioglitazone increased LXRα/ABCA1/G1 expressions, which enhanced ChE from macrophages. Inhibition of PPARγ/LXR pathways revealed that LXR was primarily involved in pioglitazone's transactivation of ABCA1 but only partially involved for ABCG1. Promoter assays showed that ABCG1 was regulated more by the promoter in intron 4 than that upstream of exon 1 but both promoters were responsive to LXR activation. Sera obtained after pioglitazone treatment promoted ChE and ABCA1/G1 expressions in macrophages. Conclusion Pioglitazone enhanced ChE from macrophages by increasing ABCA1/G1 in LXR-dependent and -independent manners. Our comparable in vitro and ex vivo results shed new light on pioglitazone's novel anti-atherogenic property. |
| Databáze: | OpenAIRE |
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