Crossover trial comparing sera obtained from diabetic patients before and after pioglitazone administration on cholesterol efflux from macrophages

Not Applicable

• Conditions: Diabetes

• Registration Number: JPRN-UMIN000004189
• Lead Sponsor: ational Defense Medical College

Brief Summary

Objective Pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma-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 inmacrophages were assessed. Then, mRNA was quantified in macrophages when PPARgamma/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 LXRalpha/ABCA1/G1 expressions, which enhanced ChE from macrophages. Inhibition of PPARgamma/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 ovel anti-atherogenic property.

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2010-09-15
• Last Update Posted: 17 October 2023

Recruitment & Eligibility

• Status: Complete: follow-up complete
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

Not provided

Exclusion Criteria

Poor-controlled diabetes (HbA1c>8.0 %)

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Macrophage ABCA1/G1 expressions and cholesterol efflux cultured under sera obtained from diabetic patients