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Science 328 (5985): 1566-1569

Copyright © 2010 by the American Association for the Advancement of Science

MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis

S. Hani Najafi-Shoushtari,1,2 Fjoralba Kristo,3 Yingxia Li,4 Toshi Shioda,1 David E. Cohen,4 Robert E. Gerszten,3,5 Anders M. Näär1,2,*

Abstract: Proper coordination of cholesterol biosynthesis and trafficking is essential to human health. The sterol regulatory element–binding proteins (SREBPs) are key transcription regulators of genes involved in cholesterol biosynthesis and uptake. We show here that microRNAs (miR-33a/b) embedded within introns of the SREBP genes target the adenosine triphosphate–binding cassette transporter A1 (ABCA1), an important regulator of high-density lipoprotein (HDL) synthesis and reverse cholesterol transport, for posttranscriptional repression. Antisense inhibition of miR-33 in mouse and human cell lines causes up-regulation of ABCA1 expression and increased cholesterol efflux, and injection of mice on a western-type diet with locked nucleic acid–antisense oligonucleotides results in elevated plasma HDL. Our findings indicate that miR-33 acts in concert with the SREBP host genes to control cholesterol homeostasis and suggest that miR-33 may represent a therapeutic target for ameliorating cardiometabolic diseases.

1 Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
3 Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
4 Department of Medicine, Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
5 Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.

* To whom correspondence should be addressed. E-mail: naar{at}helix.mgh.harvard.edu


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