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

Department of Animal Science, College of Agriculture & Life Science, Chonnam National University, Gwanju 500-757, South Korea.
Cell metabolism (Impact Factor: 17.57). 07/2013; 18(1):51-61. DOI: 10.1016/j.cmet.2013.06.010
Source: PubMed


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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    • "In colon cancer cells, miR- 182 and miR-503 were sequentially upregulated and cooperatively targeted FBXW7 for gene suppression [58]. Moreover, miR-182 could be upregulated by sterol regulatory element-binding proteins (SREBPs), and SREBP-induced miR-182 increased SREBP nuclear accumulation by downregulating FBXW7 [59], suggesting that a SREBP/miR-182 positive feedback loop may regulate intracellular lipid homeostasis and pathogenesis of liver cancer. FBXW7 is targeted by other miRNAs whose functions in tumorigenesis are more context-dependent. "
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    • "Multiple studies have demonstrated that mirNAs are regulated under metabolic stimuli and conversely control metabolism (Dumortier et al. 2013). The mirNA cluster, mir-183-96-182, has been reported to contribute to a regulatory loop intermediated by SreBP maturation for intracellular lipid homeostasis and is also thought to be regulated by SreBPs (Jeon et al. 2013). Here, we found that mir-183-96-182 cluster levels were significantly enhanced in mouse liver after treatment with PFOA. "
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    • "MicroRNAs are involved in many processes, including cell survival and death (Hutvagner et al., 2001), lipid and glucose metabolism (Jeon et al., 2013; Kornfeld et al., 2013) and tissue development (Fu et al., 2013). Human preadipocytes are a useful in vitro model for investigating adipocyte proliferation and differentiation at the molecular level (Flier, 2004). "
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