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

doi:10.1016/j.cmet.2013.06.010

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

Molecular Genetics

Research output: Contribution to journal › Article › peer-review

97 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 language	English (US)
Pages (from-to)	51-61
Number of pages	11
Journal	Cell Metabolism
Volume	18
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2013.06.010
State	Published - Jul 2 2013

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2013.06.010

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title = "An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis",

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.",

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

note = "Funding Information: This work was supported, in part, by a grant from the NHLBI/NIH (HL48044). Y.-A.M. was supported by HL020948-36. We thank R. Debose-Boyd for supplying the HMG CoA reductase and Insig-2 antibodies, J. Rutter for the FLAG-tagged SREBP-2 vector, and J. Ericsson for the GST-tagged FBXW7 expression plasmid. ",

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doi = "10.1016/j.cmet.2013.06.010",

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AU - Jeon, Tae Il

AU - Esquejo, Ryan M.

AU - Roqueta-Rivera, Manuel

AU - Phelan, Peter E.

AU - Moon, Young Ah

AU - Govindarajan, Subramaniam S.

AU - Esau, Christine C.

AU - Osborne, Timothy F.

N1 - Funding Information: This work was supported, in part, by a grant from the NHLBI/NIH (HL48044). Y.-A.M. was supported by HL020948-36. We thank R. Debose-Boyd for supplying the HMG CoA reductase and Insig-2 antibodies, J. Rutter for the FLAG-tagged SREBP-2 vector, and J. Ericsson for the GST-tagged FBXW7 expression plasmid.

PY - 2013/7/2

Y1 - 2013/7/2

N2 - 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.

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

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