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Cell Metab. 2013 Jul 2;18(1):51-61. doi: 10.1016/j.cmet.2013.06.010.

An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis.

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Metabolic Signaling and Disease Program and Diabetes and Obesity Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.


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.

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