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

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.

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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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    ABSTRACT: Perfluoroalkyl acids are widely used in numerous industrial and commercial applications due to their unique physical and chemical characteristics. Although perfluorooctanoic acid (PFOA) is associated with hepatomegaly through peroxisome proliferator-activated receptor α (PPARα) activation, liver fat accumulation and changes in gene expression related to fatty acid metabolism could still be found in PPARα-null mice exposed to PFOA. To explore the potential effects of PFOA on sterol regulatory element-binding proteins (SREBPs) activity, male mice were dosed with either Milli-Q water or PFOA at doses of 0.08, 0.31, 1.25, 5, and 20 mg/kg/day by gavage for 28 days. Liver total cholesterol concentrations and PFOA contents showed a dose-dependent decrease and increase, respectively. Transcriptional activity of PPARα and SREBPs was significantly enhanced in livers. Protein expression analyzed by Western blotting showed that PFOA exposure stimulated SREBP maturation. Furthermore, proteins blocked SREBP precursor transport, insulin-induced gene 1 (INSIG1) and INSIG2 proteins, as well as a protein-mediated nuclear SREBP proteolysis, F-box and WD-40 domain protein 7, decreased in mouse liver exposed to PFOA. The expression levels of the miR-183-96-182 cluster, which is possibly involved in a regulatory loop intermediated by SREBPs maturation, were also increased in the mouse liver after PFOA exposure. We also observed that PFOA induced lipid content and PPARα in Hepa 1-6 cells after exposure to PFOA for 72 h but SREBPs were not activated in vitro. These results demonstrated that SREBPs were maturated by activating the miR-183-96-182 cluster-SREBP regulatory loop in PFOA-exposed mouse liver.
    Archives of Toxicology 09/2015; 89(9):1569-78. DOI:10.1007/s00204-014-1322-7 · 5.98 Impact Factor
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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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    ABSTRACT: Visceral obesity is an independent risk factor for metabolic syndrome, and abnormal fat accumulation is linked to increases in the number and size of adipocytes. miR-146b was a miRNA highly expressed in mature adipocytes while very low expressed in human mesenchymal stem cells (hMSCs) and human visceral preadipocytes (vHPA). In this paper, we mainly focused on the roles of miR-146b in adipogenesis. We found miR-146b could inhibit the proliferation of visceral preadipocytes and promote their differentiation. MiR-146b in preadipocytes inhibited the expression of KLF7, a member of the Kruppel-like transcription factors, as demonstrated by a firefly luciferase reporter assay, indicating that KLF7 is a direct target of the endogenous miR-146b in human preadipocytes. MiR-146b expression was significantly altered in visceral and subcutaneous adipose tissues in human overweight and obese subjects, and in the epididymal fat tissues and brown fat tissues of diet-induced obese mice. Our data indicates that miR-146b may be a new therapeutic target against human visceral obesity and metabolic dysfunction.
    Molecular and Cellular Endocrinology 06/2014; 393(1-2). DOI:10.1016/j.mce.2014.05.022 · 4.41 Impact Factor
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    • "This means that Fbw7 plays pivotal roles in lipogenesis dominantly mediated by SREBP pathway. Additionally, Fbw7 is negatively regulated by microRNA miR-182 reciprocally, which was activated by SREBP-2 directly in mouse [49].Therefore, Fbw7-SREBP-miR-182 axis providers a regulatory loop for intracellular lipid homeostasis. "
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    ABSTRACT: To maintain cholesterol homeostasis, the processes of cholesterol metabolism are regulated at multiple levels including transcription, translation, and enzymatic activity. Recently, the regulation of protein stability of some key players in cholesterol metabolism has been characterized. More and more ubiquitin ligases have been identified including gp78, Hrd1, TRC8, TEB4, Fbw7, and inducible degrader of low density lipoprotein receptor. Their working mechanisms and physiological functions are becoming revealed. Here, we summarize the structure, substrates and function of these ubiquitin ligases. Their potential application in drug discovery is also discussed.
    Diabetes & metabolism journal 06/2014; 38(3):171-80. DOI:10.4093/dmj.2014.38.3.171
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