Cholesterol is a potent regulator of gene expression via a canonical pathway co-regulated by SREBP and Sp1. Here we establish the caveolin-1 gene promoter as a cell type-specific model for SREBP/Sp1 regulation whereby lipoprotein cholesterol depletion activates caveolin-1 transcription in endothelial type cells, but not in fibroblasts, both in vitro and in vivo. By extending this model, we describe a novel pathway distinct from the prototypical SREBP/Sp1 regulatory loop involving the Sp1-like protein, KLF11. Through a combination of RNA interference, chromatin immunoprecipitation assays, electrophoretic mobility shift assays, and reporter assays, we demonstrate that in the presence of cholesterol, KLF11 acts as a dominant repressor of the caveolin-1 gene. Mechanistically, cholesterol depletion results in displacement of KLF11 from an Sp1 site flanking an SRE, indicating that activation by SREBP/Sp1 requires antagonism of KLF11 repression. The displacement of KLF11 results from both a down-regulation of its expression and competition by Sp1 for DNA binding. Therefore, these studies identify a novel pathway whereby KLF11 repression is coordinated with Sp1/SREBP activation of cholesterol-dependent gene expression in a cell type-specific manner and outline the mechanisms by which these functions are achieved.
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