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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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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein.
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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K. Adeli (2011)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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P.-C. Ho, K.-C. Chang, Y.-S. Chuang, and L.-N. Wei (2011)
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   Abstract »    Full Text »    PDF »
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S. Behrman, D. Acosta-Alvear, and P. Walter (2011)
J. Cell Biol. 192, 919-927
   Abstract »    Full Text »    PDF »
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R. D. Cox and C. D. Church (2011)
Dis. Model. Mech. 4, 155-164
   Abstract »    Full Text »    PDF »
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A. D. Johnson and S. Prakash (2011)
Circ Cardiovasc Genet 4, 94-97
   Full Text »    PDF »
The Art of MicroRNA Research.
E. van Rooij (2011)
Circ. Res. 108, 219-234
   Abstract »    Full Text »    PDF »
MicroRNAs in Metabolism and Metabolic Diseases.
V. Rottiers, S. H. Najafi-Shoushtari, F. Kristo, S. Gurumurthy, L. Zhong, Y. Li, D. E. Cohen, R. E. Gerszten, N. Bardeesy, R. Mostoslavsky, et al. (2011)
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   Abstract »    Full Text »    PDF »
Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation.
I. Gerin, L.-A. Clerbaux, O. Haumont, N. Lanthier, A. K. Das, C. F. Burant, I. A. Leclercq, O. A. MacDougald, and G. T. Bommer (2010)
J. Biol. Chem. 285, 33652-33661
   Abstract »    Full Text »    PDF »
MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo.
T. Horie, K. Ono, M. Horiguchi, H. Nishi, T. Nakamura, K. Nagao, M. Kinoshita, Y. Kuwabara, H. Marusawa, Y. Iwanaga, et al. (2010)
PNAS 107, 17321-17326
   Abstract »    Full Text »    PDF »
HDL miR-ed Down by SREBP Introns.
M. S. Brown, J. Ye, and J. L. Goldstein (2010)
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   Abstract »    Full Text »    PDF »

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