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Science 328 (5985): 1570-1573

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

MiR-33 Contributes to the Regulation of Cholesterol Homeostasis

Katey J. Rayner,1,2,* Yajaira Suárez,1,* Alberto Dávalos,1 Saj Parathath,1 Michael L. Fitzgerald,2 Norimasa Tamehiro,2 Edward A. Fisher,1 Kathryn J. Moore,1,2,{dagger},{ddagger} Carlos Fernández-Hernando1,{dagger},{ddagger}

Abstract: Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element–binding factor–2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate–binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1. In mouse macrophages, miR-33 also targets ABCG1, reducing cholesterol efflux to nascent high-density lipoprotein (HDL). Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver, reducing circulating HDL levels. Conversely, silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. Thus, miR-33 appears to regulate both HDL biogenesis in the liver and cellular cholesterol efflux.

1 Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY 10016, USA.
2 Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

* {dagger}These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: kathryn.moore{at}nyumc.org (K.J.M.); carlos.fernandez-hernando{at}nyumc.org (C.F.-H.)

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