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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • F-Box Proteins / genetics
  • F-Box Proteins / physiology
  • F-Box-WD Repeat-Containing Protein 7
  • Genes, Regulator / genetics*
  • Genes, Regulator / physiology
  • Homeostasis / genetics*
  • Homeostasis / physiology
  • Lipid Metabolism / genetics*
  • Lipid Metabolism / physiology
  • Liver / cytology
  • Liver / metabolism
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / physiology
  • Models, Animal
  • Operon / genetics*
  • Operon / physiology
  • Sterol Regulatory Element Binding Protein 2 / genetics*
  • Sterol Regulatory Element Binding Protein 2 / physiology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / physiology

Substances

  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • Fbxw7 protein, mouse
  • Insig2 protein, mouse
  • Membrane Proteins
  • MicroRNAs
  • Mirn182 microRNA, mouse
  • Mirn96 microRNA, mouse
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 2
  • Ubiquitin-Protein Ligases