MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis.
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.
Najafi-Shoushtari
S Hani
SH
Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
Kristo
Fjoralba
F
Li
Yingxia
Y
Shioda
Toshi
T
Cohen
David E
DE
Gerszten
Robert E
RE
Näär
Anders M
AM
D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood*; D004032:Diet; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D007438:Introns; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D034622:RNA Interference; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D020413:3' Untranslated Regions; C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D016376:Oligonucleotides, Antisense; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol
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