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

Tae Il Jeon, Ryan M. Esquejo, Manuel Roqueta-Rivera, Peter E. Phelan, Young Ah Moon, Subramaniam S. Govindarajan, Christine C. Esau, Timothy F. Osborne

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)51-61
Number of pages11
JournalCell Metabolism
Volume18
Issue number1
DOIs
StatePublished - Jul 2 2013

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Jeon, T. I., Esquejo, R. M., Roqueta-Rivera, M., Phelan, P. E., Moon, Y. A., Govindarajan, S. S., Esau, C. C., & Osborne, T. F. (2013). An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis. Cell Metabolism, 18(1), 51-61. https://doi.org/10.1016/j.cmet.2013.06.010