Abstract
Pioglitazone, a hypoglycemic agent, has been shown to increase plasma HDL cholesterol, but the mechanism is incompletely understood. We further investigated effects of pioglitazone on transcriptional regulation of apolipoprotein (apo)A-I gene and functional properties of pioglitazone-induced apoA-I-containing particles. Pioglitazone dose-dependently stimulated apoA-I promoter activities in HepG2 cells. A peroxisome proliferator-activated receptor (PPAR)-response element located in site A (-214 to -192 bp, upstream of the transcription start site) of the promoter is required for pioglitazone-induced apoA-I gene transcription. Deletion of site A (-214 to -192 bp), B (-169 to -146 bp), or C (-134 to -119 bp), which clusters a number of cis-acting elements for binding of different transcription factors, reduced the basal apoA-I promoter activities, and no additional pioglitazone-sensitive elements were found within this region. Overexpression or knock-down of liver receptor homolog-1, a newly identified nuclear factor with strong stimulatory effect on apoA-I transcription, did not alter pioglitazone-induced apoA-I transcription. Pioglitazone-induced apoA-I transcription is mainly mediated through PPARalpha but not PPARgamma in hepatocytes. Pioglitazone induced production of HDL enriched in its subfraction containing apoA-I without apoA-II, which inhibited monocyte adhesion to endothelial cells in vitro. In conclusion, pioglitazone increases apoA-I production by directly enhancing PPAR-response element-dependent transcription, resulting in generation of apoA-I-containing HDL particles with increased anti-inflammatory property.
Highlights
Pioglitazone, a hypoglycemic agent, has been shown to increase plasma HDL cholesterol, but the mechanism is incompletely understood
A number of clinical studies established that pioglitazone significantly increased serum HDL-cholesterol and decreased triglycerides, and pioglitazone produced more favorable lipid profiles than rosiglitazone in patients with type 2 diabetes [23,24,25,26]
In an attempt to understand the mechanisms of apoA-I increase by pioglitazone, using human hepatoblasoma cell line (HepG2 cells), we have previously shown that pioglitazone increased the de novo synthesis and secretion of apoA-I particles in the culture medium by increasing apoA-I mRNA levels without affecting HDL catabolic events in HepG2 cells [16]
Summary
Pioglitazone, a hypoglycemic agent, has been shown to increase plasma HDL cholesterol, but the mechanism is incompletely understood. SiRNA knocking-down LRH-1 reduced LRH-1 mRNA expression by 55% [RT and quantitative real-time PCR (RT-qPCR) fold change: 0.443 ± 0.145 vs control 1.0 ± 0; P < 0.01) and decreased apoA-I transcription, but did not affect pioglitazone-induced activity, as pioglitazone increased apoA-I transcription by 162% and 168% in control and siRNA-treated cells, respectively, suggesting that LRH-1, with its binding element in site C, is not involved in pioglitazone-induced apoA-I transcription (Fig. 5B).
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