MiR-181a regulates lipid metabolism via IDH1

Chu, Bo; Wu, Ting; Ma, Lin; Mei, Yide; Wu, Mian

doi:10.1038/srep08801

Cited by 54 publications

(43 citation statements)

References 34 publications

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“…Transgenic IDH1 expression in liver and adipose tissues promoted hyperlipidemia and obesity, paralleled by increased triglyceride and cholesterol content (Koh et al, 2004). Conversely, in vivo IDH1 ablation resulted in weight loss associated with reduced fat mass and circulating triglyceride levels (Nam et al, 2012; Chu et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

et al. 2017

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Summary Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBM. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs survival of animal subjects bearing patient-derived xenografts (PDXs). On a molecular level, diminished IDH1 activity results in reduced α-ketoglutarate (αKG) and NADPH production, paralleled by deficient carbon flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common metabolic adaptation by GBM to support macromolecular synthesis, aggressive growth, and therapy resistance.

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Section: Discussionmentioning

confidence: 99%

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

et al. 2017

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“…H, Western blots of hepatic SREBP1 and FAS. **, p Ͻ 0.01; ***, p Ͻ 0.001. n ϭ 6. hydrogenase 1 (IDH1), a novel metabolic enzyme in the TCA cycle (32). In this study, using miRNA analysis of the livers of db/db mice and HFD-fed mice and NCTC1469 cells treated with an oleic acid/palmitic acid mixture, we examined the role of miR-291b-3p which belongs to the murine miR-290 cluster, in lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Liver MicroRNA-291b-3p Promotes Hepatic Lipogenesis through Negative Regulation of Adenosine 5′-Monophosphate (AMP)-activated Protein Kinase α1

Meng

Guo

Fang

et al. 2016

Journal of Biological Chemistry

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In a microarray study, we found that hepatic miR-291b-3p was significantly increased in leptin-receptor-deficient type 2 mice (db/db), a mouse model of diabetes. The function of miR291b-3p is unknown. The potential role of miR-291b-3p in regulating hepatic lipid metabolism was explored in this study. High-fat diet (HFD)-and chow-fed mice were injected with an adenovirus expressing a miR-291b-3p inhibitor and a miR291b-3p mimic through the tail vein. Hepatic lipids and lipogenic gene expression were analyzed. Additionally, gain-and loss-of-function studies were performed in vitro to identify direct targets of miR-291b-3p. MiR-291b-3p expression and the protein levels of sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) were increased in the steatotic liver of db/db mice and HFD-fed mice versus their respective controls. Inhibition of hepatic miR-291b-3p expression prevented increases in hepatic lipogenesis and steatosis in HFD-fed mice. The opposite was observed when miR-291b-3p was overexpressed in the livers of chow-fed C57BL/6J wild-type mice. In vitro studies revealed that silencing of miR-291b-3p in NCTC1469 hepatic cells ameliorated oleic acid/palmitic acid mixture-induced elevation of cellular triglycerides. Importantly, we identified AMP-activated protein kinase (AMPK)-␣1 as a direct target of miR-291b-3p. Using metformin, an activator of AMPK, we showed that AMPK activation-induced inhibition of hepatic lipid accumulation was accompanied by reduced expression of miR-291b-3p in the liver. Liver miR-291b-3p promoted hepatic lipogenesis and lipid accumulation in mice. AMPK␣1 is a direct target of miR-291b-3p. In conclusion, our findings indicate that miR-291b-3p promotes hepatic lipogenesis by suppressing AMPK␣1 expression and activity, indicating the therapeutic potential of miR-291b-3p inhibitors in fatty liver disease.

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“…miR‐181a targets the inflammatory genes IL‐1α (Xie et al, ), TNF (He et al, ) and the transcriptional factor C/EBPα but also suppresses Kruppel‐like factor 6 (KLF6) (Bi et al, ), a PPAR‐γ inhibitor (Date et al, ), thus likely favoring PPAR‐γ‐dependent energy metabolism in mitochondria and fatty acid peroxidation in microglia. This has been proven in lymphocytes where miR‐181a enhances the expression of genes involved in beta oxidation while suppresses isocitrate dehydrogenase 1 (IDH1), a cytoplasmic enzyme involved in production of NADPH, the cofactor for NO and superoxide generation (Lian et al, ; Chu, Wu, Miao, Mei, & Wu, ; Table ).…”

Section: Micrornas Promoting Pro‐regenerative Microglia Phenotype Andmentioning

confidence: 99%

How to reprogram microglia toward beneficial functions

Fumagalli

Lombardi

Gressèns

et al. 2018

Glia

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Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.

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MiR-181a regulates lipid metabolism via IDH1

Cited by 54 publications

References 34 publications

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

Liver MicroRNA-291b-3p Promotes Hepatic Lipogenesis through Negative Regulation of Adenosine 5′-Monophosphate (AMP)-activated Protein Kinase α1

How to reprogram microglia toward beneficial functions

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