Abstract

Cholesterol homeostasis is regulated by a family of transcription factors designated sterol regulatory element-binding proteins (SREBPs). Precise control of SREBP-targeted genes requires additional interactions with co-regulatory transcription factors. In the case of the low density lipoprotein receptor (LDLR), SREBP cooperates with the specificity protein Sp1 to activate the promoter. In this report, we describe a novel pathway in LDLR transcriptional regulation distinct from the SREBP-Sp1 activation complex involving the Sp1-like protein Krueppel-like factor 13 (KLF13). Using a combination of RNA interference, electrophoretic mobility shift, chromatin immunoprecipitation, and reporter assays, deletion, and site-directed mutagenesis, we demonstrated that KLF13 mediates repression in a DNA context-selective manner. KLF13 repression of LDLR promoter activity appears to be needed to keep the receptor silent, a state that can be antagonized by Sp1, SREBP, and inhibitors of histone deacetylase activity. Chromatin immunoprecipitation assay confirmed that KLF13 binds proximal LDLR DNA sequences in vivo and that exogenous oxysterol up-regulates such binding. Together these studies identify a novel regulatory pathway in which gene repression by KLF13 must be overcome by the Sp1-SREBP complex to activate the LDLR promoter. Therefore, these data should replace a pre-existent and more simple paradigm that takes into consideration only the induction of the activator proteins Sp1-SREBP as necessary for LDLR promoter drive without including default repression, such as that by KLF13, of the LDLR gene.

Highlights

  • Phocellulose-binding specificity (Sp) proteins and 16 Krueppel-like factors (KLFs), which regulate facets of embryonic development, cellular proliferation, apoptosis, differentiation, and oncogenesis (4 – 8)

  • Krueppel-like factor 13 (KLF13) acts as a potent transcriptional repressor of the low density lipoprotein (LDLR) promoter, wherein transcriptional inhibition is antagonized by Sp1, sterol regulatory element-binding protein (SREBP), and histone deacetylases (HDACs) inhibitors

  • During the last three decades, transcriptional regulation of the LDLR promoter has been demonstrated to be critical for cholesterol metabolism, such that hypercholesterolemic diseases arise from attendant defects

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Summary

Introduction

Phocellulose-binding specificity (Sp) proteins and 16 KLFs, which regulate facets of embryonic development, cellular proliferation, apoptosis, differentiation, and oncogenesis (4 – 8). Our data support a model in which KLF13 silences the LDLR promoter, unless the SREBP-Sp1 complex antagonizes repression and mediates transcriptional activation.

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