An SREBP-Responsive microRNA Operon Contributes to a Regulatory Loop for Intracellular Lipid Homeostasis

• DOI: 10.1016/j.cmet.2013.06.010
• Publication Date: 2013-07-02T15:41:26Z
• Authors: Tae-Il Jeon; Ryan M. Esquejo; Manuel Roqueta-Ri...; Peter E. Phelan; Young-Ah Moon; Subramaniam S. Go...; Christine C. Esau; Timothy F. Osborne
• Keywords: Male; 0301 basic medicine; F-Box-WD Repeat-Containing Protein 7; Physiology; F-Box Proteins; Ubiquitin-Protein Ligases; Membrane Proteins; Cell Biology; Lipid Metabolism; Mice, Inbred C57BL; Mice; MicroRNAs; 03 medical and health sciences; Liver; Genes, Regulator; Models, Animal; Operon; Animals; Homeostasis; Molecular Biology; Cells, Cultured; Sterol Regulatory Element Binding Protein 2

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.