Abstract
Sterol regulatory element-binding proteins (SREBPs) have evolved as a focal point for linking lipid synthesis with other pathways that regulate cell growth and survival. Here, we have uncovered a polycistrionic microRNA (miRNA) locus that is activated directly by SREBP-2. Two of the encoded miRNAs, miR-182 and miR-96, negatively regulate the expression of Fbxw7 and Insig-2, respectively, and both are known to negatively affect nuclear SREBP accumulation. Direct manipulation of this miRNA pathway alters nuclear SREBP levels and endogenous lipid synthesis. Thus, we have uncovered a mechanism for the regulation of intracellular lipid metabolism mediated by the concerted action of a pair of miRNAs that are expressed from the same SREBP-2-regulated miRNA locus, and each targets a different protein of the multistep pathway that regulates SREBP function. These studies reveal an miRNA "operon" analogous to the classic model for genetic control in bacterial regulatory systems.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cells, Cultured
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F-Box Proteins / genetics
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F-Box Proteins / physiology
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F-Box-WD Repeat-Containing Protein 7
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Genes, Regulator / genetics*
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Genes, Regulator / physiology
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Homeostasis / genetics*
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Homeostasis / physiology
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Lipid Metabolism / genetics*
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Lipid Metabolism / physiology
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Liver / cytology
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Liver / metabolism
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Male
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Membrane Proteins / genetics
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Membrane Proteins / physiology
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Mice
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Mice, Inbred C57BL
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MicroRNAs / genetics*
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MicroRNAs / physiology
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Models, Animal
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Operon / genetics*
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Operon / physiology
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Sterol Regulatory Element Binding Protein 2 / genetics*
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Sterol Regulatory Element Binding Protein 2 / physiology
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / physiology
Substances
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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Fbxw7 protein, mouse
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Insig2 protein, mouse
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Membrane Proteins
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MicroRNAs
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Mirn182 microRNA, mouse
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Mirn96 microRNA, mouse
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Srebf2 protein, mouse
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Sterol Regulatory Element Binding Protein 2
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Ubiquitin-Protein Ligases