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Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor implicated in adipocyte differentiation and insulin sensitivity. We investigated whether PPARγ expression is dependent on the activity of adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1 (ADD-1/SREBP-1), another transcription factor associated with both adipocyte differentiation and cholesterol homeostasis. Ectopic expression of ADD-1/SREBP-1 in 3T3-L1 and HepG2 cells induced endogenous PPARγ mRNA levels. The related transcription factor SREBP-2 likewise induced PPARγ expression. In addition, cholesterol depletion, a condition known to result in proteolytic activation of transcription factors of the SREBP family, induced PPARγ expression and improved PPRE-driven transcription. The effect of the SREBPs on PPARγ expression was mediated through the PPARγ1 and -3 promoters. Both promoters contain a consensus E-box motif that mediates the regulation of the PPARγ gene by ADD-1/SREBP-1 and SREBP-2. These results suggest that PPARγ expression can be controlled by the SREBP family of transcription factors and demonstrate new interactions between transcription factors that can regulate different pathways of lipid metabolism.
ACKNOWLEDGMENTS
The technical help of D. Cayet and C. Haby and the support of and/or discussion with A. Negro-Villar, R. Heyman, M. Leibowitz, D. Moller, S. Wright, and D. De Chaffoy are kindly acknowledged. We acknowledge the gift of materials from Samuel Wright and Alex Nadzan.
This work was supported by grants from INSERM, Région Nord-Pas-de-Calais, Institut Pasteur, Université de Lille II, ARC (no. 6403), and Ligand pharmaceuticals. J.A. is a research director with the CNRS, and K.S. is a research assistant with INSERM. L.F. was supported by the Janssen Research Foundation.