| First Author | Jitrapakdee S | Year | 2005 |
| Journal | J Biol Chem | Volume | 280 |
| Issue | 29 | Pages | 27466-76 |
| PubMed ID | 15917242 | Mgi Jnum | J:100817 |
| Mgi Id | MGI:3589695 | Doi | 10.1074/jbc.M503836200 |
| Citation | Jitrapakdee S, et al. (2005) The peroxisome proliferator-activated receptor-gamma regulates murine pyruvate carboxylase gene expression in vivo and in vitro. J Biol Chem 280(29):27466-76 |
| abstractText | Pyruvate carboxylase (PC) plays a crucial role in various metabolic pathways, including gluconeogenesis, lipogenesis, and glucose-induced insulin secretion. Here we showed for the first time that the PC gene is transcriptionally regulated by peroxisome proliferator-activated receptor-gamma (PPARgamma) in vitro and in vivo in white and brown adipose tissue. PC mRNA and protein are markedly increased during differentiation of 3T3-L1 cells and HIB-1B, in parallel with the expression of the adipogenic transcription factors, CCAAT-enhancer binding protein alpha, PPARgamma1, and PPARgamma2. Tumor necrosis factor-alpha, a cytokine that blocks differentiation of 3T3-L1 cells, suppressed PC expression. Co-transfection studies in 3T3-L1 preadipocytes or HEK293T cells with a 2.3-kb promoter fragment of mouse PC gene linked to a luciferase reporter construct and with plasmids overexpressing retinoid X receptor alpha/PPARgamma1 or retinoid X receptor alpha/PPARgamma2 showed a 6-8-fold increase above the basal promoter activity. Furthermore, treatment of these transfected cells with the PPARgamma agonist doubled the promoter activity. Mutation of the putative PPAR-response element-(-386/-374) of this 2.3-kb PC promoter fragment abolished the PPARgamma response. Gel shift and chromatin immunoprecipitation assays demonstrated that endogenous PPARgamma binds to this functional PPAR-response element of the PC promoter. Mice with targeted disruption of the PPARgamma2 gene displayed approximately 50-60% reduction of PC mRNA and protein in white adipose tissue. Similarly, in brown adipose tissue of PPARgamma2-deficient mice subjected to cold exposure, PC mRNA was 40% lower than that of wild type mice. Impaired in vitro differentiation of white adipocytes of PPARgamma2 knock-out mice was also associated with a marked reduction of PC mRNA. Our findings identified PC as a PPARgamma-regulated gene and suggested a role for PPARgamma regulating intermediary metabolism. |
