Adipocyte low density lipoprotein receptor-related protein gene expression and function is regulated by peroxisome...

The alpha(2)-macroglobulin receptor/low density lipoprotein receptor-related protein (LRP) is a large multifunctional receptor that interacts with a variety of molecules. It is implicated in biologically important processes such as lipoprotein metabolism, neurological function, tissue remodeling, protease complex clearance, and cell signal transduction. However, the regulation of LRP gene expression remains largely unknown. In this study, we have analyzed 2 kb of the 5'-flanking region of the LRP gene and identified a predicted peroxisome proliferator response element (PPRE) from -1185 to -1173. Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands such as fatty acids and rosiglitazone increased functional cell surface LRP by 1.5-2.0-fold in primary human adipocytes and in the SW872 human liposarcoma cell line as assessed by activated alpha(2)-macroglobulin binding and degradation. These agents were found to increase LRP transcription. Gel shift analysis of the putative PPRE demonstrated direct binding of PPARgamma/retinoid X receptor alpha heterodimers to the PPRE in the LRP gene. Furthermore, these heterodimers could no longer interact with a mutated PPRE probe. The isolated promoter was functional in SW872 cells, and its activity was increased by 1.5-fold with the addition of rosiglitazone. Furthermore, the isolated response element was similarly responsive to rosiglitazone when placed upstream of an ideal promoter. Mutagenesis of the predicted PPRE abolished the ability of this construct to respond to rosiglitazone. These data demonstrate that fatty acids and rosiglitazone directly stimulate transcription of the LRP gene through activation of PPARgamma and increase functional LRP expression.