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

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

doi:10.1016/j.cmet.2013.06.010

Cited by 102 publications

(109 citation statements)

References 48 publications

(74 reference statements)

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“…These results demonstrated that proteins involved in blocking SreBPs transport and nuclear SreBPs degradation all decreased in livers of mice after 28-day exposure to PFOA, indicating the activation of the SreBP maturation pathway. earlier research determined that a SreBP-controlling mirNA cluster, mir-183-96-182, was involved in a regulatory loop intermediated by SreBP maturation (Jeon et al 2013). using TaqMan mirNA assay, we also found a significant increase in the expression level of the mir-183-96-182 cluster (Fig.…”

Section: Pfoa Changed Lipid Content and Activated Ppars In Mouse Livermentioning

confidence: 97%

Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

2014

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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.

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Section: Pfoa Changed Lipid Content and Activated Ppars In Mouse Livermentioning

confidence: 97%

Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

2014

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“…SREBP2 directly activates miR-182 and miR-96, which negatively regulate the expression of FBXW7 and INSIG-2, respectively. These genes affect nuclear SREBP levels and endogenous lipid synthesis (29), potentially leading to steatohepatitis (59). Furthermore, several miRNAs directly contribute to liver expression of miR-33 targets, including ABCA1 (target of miR-26, miR-128-2, miR-144) (1, 9, 27, 75), ABCG1 (target of miR-128-2) (1), and CPT1A (target of miR-370) (27).…”

Section: Impact Of Mirnas On Liver Insulin Sensitivity and In The Metmentioning

confidence: 99%

Biological roles of microRNAs in the control of insulin secretion and action

Caldérari

Diawara

Garaud

et al. 2017

Physiological Genomics

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microRNAs (miRNAs) are intracellular and circulating molecular components contributing to genome expression control through binding mRNA targets, which generally results in downregulated mRNA expression. One miRNA can target several mRNAs, and one transcript can be targeted by several miRNAs, resulting in complex fine-tuning of regulation of gene networks and signaling pathways. miRNAs regulate metabolism, adipocyte differentiation, pancreatic development, β-cell mass, insulin biosynthesis, secretion, and signaling, and their role in diabetes and obesity is emerging. Their pathophysiological effects are essentially dependent on cellular coexpression with their mRNA targets, which can show tissue-specific transcriptional responses to disease conditions and environmental challenges. Current knowledge of miRNA biology and their impact on the pathogenesis of diabetes and obesity is based on experimental data documenting miRNA expression generally in single tissue types that can be correlated with expression of target mRNAs to integrate miRNA in functional pathways and gene networks. Here we present results from the most significant studies dealing with miRNA function in liver, fat, skeletal muscle, and endocrine pancreas and their implication in diabetes and obesity

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“…Recently, the miR-183/96/182 cluster has been demonstrated to positively regulate cholesterol biosynthesis in liver cells by inhibiting expression of ISIG2 and FBXW7 [51][52][53], which encode factors that negatively regulate SREBF2. Because mature miR-183, miR-96, and miR-182 are either not detected or at very low levels in Dgcr8 +/-NSCs (Supplementary Table S2), it is unlikely that the absence of the miR-183/96/ 182 cluster is responsible for the reduced cholesterol biosynthesis in Dgcr8 -/-NSCs.…”

Section: Dgcr8mentioning

confidence: 99%

Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells

Liu

Zhang

Khodadadi‐Jamayran

et al. 2017

Stem Cells and Development

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Neural stem cells (NSCs) have the capacity to differentiate into neurons, astrocytes, and oligodendrocytes, and therefore represent a promising donor tissue source for treating neurodegenerative diseases and repairing injuries of the nervous system. However, it remains unclear how canonical microRNAs (miRNAs), the subset of miRNAs requiring the Drosha-Dgcr8 microprocessor and the type III RNase Dicer for biogenesis, regulate NSCs. In this study, we established and characterized Dgcr8 -/-NSCs from conditionally Dgcr8-disrupted mouse embryonic brain. RNA-seq analysis demonstrated that disruption of Dgcr8 in NSCs causes a complete loss of canonical miRNAs and an accumulation of pri-miRNAs. Dgcr8-/-NSCs can be stably propagated in vitro, but progress through the cell cycle at reduced rates. When induced for differentiation, Dgcr8-/-NSCs failed to differentiate into neurons, astrocytes, or oligodendrocytes under permissive conditions. Compared to Dgcr8 +/-NSCs, Dgcr8 -/-NSCs exhibit significantly increased DNA damage. Comparative RNA-seq analysis and gene set enrichment analysis (GSEA) revealed that Dgcr8 -/-NSCs significantly downregulate genes associated with neuronal differentiation, cell cycle progression, DNA replication, protein translation, and DNA damage repair. Furthermore, we discovered that Dgcr8 -/-NSCs significantly downregulate genes responsible for cholesterol biosynthesis and demonstrated that Dgcr8 -/-NSCs contain lower levels of cholesterol. Together, our data demonstrate that canonical miRNAs play essential roles in enabling lineage specification, protecting DNA against damage, and promoting cholesterol biosynthesis in NSCs.

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

Cited by 102 publications

References 48 publications

Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

Biological roles of microRNAs in the control of insulin secretion and action

Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells

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