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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP Binding Cassette Transporter, Subfamily G, Member 1
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Apolipoprotein A-I / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line
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Cholesterol / metabolism*
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Cholesterol, Dietary / administration & dosage
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Dietary Fats / administration & dosage
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Gene Expression Regulation
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Homeostasis
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Humans
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Hypercholesterolemia / genetics
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Hypercholesterolemia / metabolism
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Intracellular Signaling Peptides and Proteins
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Introns
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Lipoproteins / genetics
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Lipoproteins / metabolism
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Lipoproteins, HDL / blood
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Lipoproteins, HDL / metabolism*
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Liver / metabolism*
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Macrophages / metabolism
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Macrophages, Peritoneal / metabolism
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Niemann-Pick C1 Protein
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Proteins / genetics
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Proteins / metabolism
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Sterol Regulatory Element Binding Protein 2 / genetics
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Sterol Regulatory Element Binding Protein 2 / metabolism
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Transfection
Substances
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ABCA1 protein, human
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ABCG1 protein, mouse
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APOA1 protein, human
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ATP Binding Cassette Transporter 1
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ATP Binding Cassette Transporter, Subfamily G, Member 1
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ATP-Binding Cassette Transporters
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Apolipoprotein A-I
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Carrier Proteins
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Cholesterol, Dietary
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Dietary Fats
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Intracellular Signaling Peptides and Proteins
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Lipoproteins
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Lipoproteins, HDL
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Membrane Glycoproteins
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MicroRNAs
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Mirn33 microRNA, mouse
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NPC1 protein, human
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Niemann-Pick C1 Protein
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Npc1 protein, mouse
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Proteins
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Srebf2 protein, mouse
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Sterol Regulatory Element Binding Protein 2
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Cholesterol