Pioglitazone increases apolipoprotein A-I production by directly enhancing PPRE-dependent transcription in HepG2 cells
| Autor: | Moti L. Kashyap, Vaijinath S. Kamanna, Xi-Ming Xiong, Lin-Hua Zhang, Shobha H. Ganji |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Apolipoprotein B Transcription Genetic Peroxisome Proliferator-Activated Receptors nuclear receptors Peroxisome proliferator-activated receptor QD415-436 Response Elements Biochemistry Monocytes chemistry.chemical_compound Endocrinology Transcription (biology) Internal medicine medicine Transcriptional regulation polycyclic compounds Cell Adhesion Humans Hypoglycemic Agents PPAR alpha HDL/metabolism Transcription factor Aorta Research Articles chemistry.chemical_classification biology Apolipoprotein A-I Base Sequence Pioglitazone Cholesterol cholesterol nutritional and metabolic diseases Endothelial Cells Cell Biology Hep G2 Cells Cell biology Nuclear receptor chemistry Culture Media Conditioned biology.protein lipids (amino acids peptides and proteins) Thiazolidinediones atherosclerosis Lipoproteins HDL medicine.drug |
| Zdroj: | Journal of Lipid Research, Vol 51, Iss 8, Pp 2211-2222 (2010) |
| ISSN: | 1539-7262 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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