| First Author | Bonofiglio D | Year | 2013 |
| Journal | Biochim Biophys Acta | Volume | 1831 |
| Issue | 6 | Pages | 1027-36 |
| PubMed ID | 23370576 | Mgi Jnum | J:202439 |
| Mgi Id | MGI:5519024 | Doi | 10.1016/j.bbalip.2013.01.014 |
| Citation | Bonofiglio D, et al. (2013) Mechanisms of divergent effects of activated peroxisome proliferator-activated receptor-gamma on mitochondrial citrate carrier expression in 3T3-L1 fibroblasts and mature adipocytes. Biochim Biophys Acta 1831(6):1027-36 |
| abstractText | The citrate carrier (CIC), a nuclear-encoded protein located in the mitochondrial inner membrane, plays an important metabolic role in the transport of acetyl-CoA from the mitochondrion to the cytosol in the form of citrate for fatty acid and cholesterol synthesis. Citrate has been reported to be essential for fibroblast differentiation into fat cells. Because peroxisome proliferator-activated receptor-gamma (PPARgamma) is known to be one of the master regulators of adipogenesis, we aimed to study the regulation of CIC by the PPARgamma ligand rosiglitazone (BRL) in 3T3-L1 fibroblasts and in adipocytes. We demonstrated that BRL up-regulated CIC mRNA and protein levels in fibroblasts, while it did not elicit any effects in mature adipocytes. The enhancement of CIC levels upon BRL treatment was reversed using the PPARgamma antagonist GW9662, addressing how this effect was mediated by PPARgamma. Functional experiments using a reporter gene containing rat CIC promoter showed that BRL enhanced CIC promoter activity. Mutagenesis studies, electrophoretic-mobility-shift assay and chromatin-immunoprecipitation analysis revealed that upon BRL treatment, PPARgamma and Sp1 are recruited on the Sp1-containing region within the CIC promoter, leading to an increase in CIC expression. In addition, mithramycin, a specific inhibitor for Sp1-DNA binding activity, abolished the PPARgamma-mediated up-regulation of CIC in fibroblasts. The stimulatory effects of BRL disappeared in mature adipocytes in which PPARgamma/Sp1 complex recruited SMRT corepressor to the Sp1 site of the CIC promoter. Taken together, our results contribute to clarify the molecular mechanisms by which PPARgamma regulates CIC expression during the differentiation stages of fibroblasts into mature adipocytes. |
