miR-33 links SREBP-2 induction to repression of sterol transporters

Tyler J. Marquart, Ryan M. Allen, Daniel S. Ory, Ángel Baldán

Research output: Contribution to journalArticle

392 Scopus citations

Abstract

The sterol regulatory element binding protein 2 (SREBP-2) and the liver X receptor (LXR) control antagonistic transcriptional programs that stimulate cellular cholesterol uptake and synthesis, and cholesterol efflux, respectively. The clinical importance of SREBP-2 is revealed in patients with hypercholesterolemia treated with statins, which reduce low-density lipoprotein (LDL) cholesterol levels by increasing hepatic expression of SREBP-2 and its target, the LDL receptor. Here we show that miR-33 is encoded within SREBP-2 and that bothmRNAs are coexpressed.Wealso identify sequences in the 3′ UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for miR-33-mediated silencing. Our data show that LXR-dependent cholesterol efflux to both ApoAI and serumisameliorated by miR-33 overexpression and, conversely, stimulated by miR-33 silencing. Finally, we show that ABCA1 mRNA and protein and plasma HDL levels decline after hepatic overexpression of miR-33, whereas they increase after hepatic miR-33 silencing. These results suggest novel ways to manage hypercholesterolemic patients.

Original languageEnglish
Pages (from-to)12228-12232
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number27
DOIs
StatePublished - Jul 6 2010

Keywords

  • ABCA1
  • ABCG1
  • Cholesterol
  • High-density lipoprotein
  • miRNA

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