Pioglitazone increases apolipoprotein A-I production by directly enhancing PPRE-dependent transcription in HepG2 cells.
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.
Zhang
Lin-Hua
LH
Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA 90822, USA.
Kamanna
Vaijinath S
VS
Ganji
Shobha H
SH
Xiong
Xi-Ming
XM
Kashyap
Moti L
ML
D001011:Aorta / Q000166:cytology; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics*; D001483:Base Sequence; D002448:Cell Adhesion / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000737:chemistry; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics* / Q000378:metabolism; D000077205:Pioglitazone; D020218:Response Elements; D045162:Thiazolidinediones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
D016632:Apolipoprotein A-I; D017077:Culture Media, Conditioned; D007004:Hypoglycemic Agents; D008075:Lipoproteins, HDL; D047493:PPAR alpha; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077205:Pioglitazone