MiR-214 Promotes the Alcohol-Induced Oxidative Stress via Down-Regulation of Glutathione Reductase and Cytochrome P450 Oxidoreductase in Liver Cells

Dong, Xinxin; Liu, Hong; Chen, Fangjie; Li, Dejun; Zhao, Yanyan

doi:10.1111/acer.12209

Cited by 72 publications

(45 citation statements)

References 38 publications

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“…Consistent with this, a let-7b mimic was found to protect against oxidative stress-induced cell death in the hepatic cell line Huh7 [40]. A few other studies using hepatoma cells and/or primary hepatocytes have shown other interesting findings concerning the roles of miRNAs in hepatocyte injury [20,41,42]. It was reported in one example that miR-199a-5p protects against bile acid-induced hepatocyte damage by reducing expression of ER stress signaling proteins [20].…”

Section: Micrornas In the Mechanisms Of Dilimentioning

confidence: 78%

“…It was reported in one example that miR-199a-5p protects against bile acid-induced hepatocyte damage by reducing expression of ER stress signaling proteins [20]. Another group found that miR-214 is induced by ethanol exposure in both rats and cultured cells and that it targets glutathione reductase and cytochrome P450 oxidoreductase, thereby increasing oxidative stress and injury [41]. It has also been shown that oxidative stress itself, frequently caused by hepatotoxicants, can activate the cell death protein Rab38 in L02 cells, and that miR-124 targets Rab38 and reduces its expression [42].…”

Section: Micrornas In the Mechanisms Of Dilimentioning

confidence: 99%

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MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

McGill

Jaeschke

2015

JCM

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Drug-induced liver injury (DILI) is major problem for both the drug industry and for clinicians. There are two basic categories of DILI: intrinsic and idiosyncratic. The former is the chief cause of acute liver failure in several developed countries, while the latter is the most common reason for post-marketing drug withdrawal and a major reason for failure to approve new drugs in the U.S. Although considerably more progress has been made in the study of intrinsic DILI, our understanding of both forms of drug hepatotoxicity remains incomplete. Recent work involving microRNAs (miRNAs) has advanced our knowledge of DILI in two ways: 1) possible roles of miRNAs in the pathophysiological mechanisms of DILI have been identified and 2) circulating miRNA profiles have shown promise for the detection and diagnosis of DILI in clinical settings. The purpose of this review is to summarize major findings in these two areas of research. Taken together, exciting progress has been made in the study of miRNAs in DILI. Possible mechanisms through which miRNA species contribute to the basic mechanisms of DILI are beginning to emerge, and new miRNA-based biomarkers have the potential to greatly improve diagnosis of liver injury and prediction of patient outcomes.

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Section: Micrornas In the Mechanisms Of Dilimentioning

confidence: 78%

Section: Micrornas In the Mechanisms Of Dilimentioning

confidence: 99%

MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

McGill

Jaeschke

2015

JCM

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“…GR. In this regard miR-214 was also shown to enhance alcohol-induced oxidative stress in liver cells by binding to GR and P450 reductase mRNAs [63]. Overall there is increasing evidence on the functional importance of miRNAs in the regulation of GSH levels, either by directly targeting its synthetic machinery or by interfering with routes related to its recycling or participation in critical GSH-dependent homeostatic pathways, which are essential for the maintenance of the cellular redox state.…”

Section: Micrornas Targeting Glutathione Synthesis/metabolismmentioning

confidence: 99%

MicroRNA-mediated regulation of glutathione and methionine metabolism and its relevance for liver disease

Mato

Espinosa‐Díez

et al. 2016

Free Radical Biology and Medicine

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The discovery of the microRNA (miRNA) family of small RNAs as fundamental regulators of post-transcriptional gene expression has fostered research on their importance in every area of biology and clinical medicine. In the particular area of liver metabolism and disease, miRNAs are gaining increasing importance. By focusing on two fundamental hepatic biosynthetic pathways, glutathione and methionine, we review recent advances on the comprehension of the role of miRNAs in liver pathophysiology and more specifically of models of hepatic cholestasis/fibrosis and hepatocellular carcinoma.

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“…Accumulation of lipid products such as triglycerides in hepatocytes leads to lipid superoxidation and oxidative stress, resulting in apoptosis, and hepatic inflammation [7]. microRNAs (miRNAs) are shown to modulated by alcohol in the liver and in hepatocytes to exert inflammatory and fat accumulation effects [6, 8–10]. Among other miRNAs, miR-155 is a major regulator of immune responses [11].…”

Section: Introductionmentioning

confidence: 99%

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

Bala

Csák

Saha

et al. 2016

Journal of Hepatology

239

270

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Background & Aims Alcoholic liver disease (ALD) ranges from fatty liver to inflammation and cirrhosis. miRNA-155 is an important regulator of inflammation. In this study, we describe the in vivo role of miR-155 in ALD. Methods Wild type, WT (C57/BL6J) or miR-155 KO and TLR4 KO mice received Lieber-DeCarli diet for 5 weeks. Some mice received corn oil or CCl4 for 2 or 9 weeks. Results We found that miR-155 KO mice are protected from alcohol-induced steatosis and inflammation. The reduction in alcohol-induced fat accumulation in miR-155 KO mice was associated with increased PPRE and PPARα (miR-155 target) binding and decreased MCP1 production. Treatment with a miR-155 inhibitor increased PPARγ expression in naive and alcohol treated RAW macrophages. Alcohol increased lipid metabolism genes (FABP4, LXRα, ACC1 and LDLR) in WT mice and this was prevented in KO mice. Alcohol diet induced increase in the number of CD163+CD206+ infiltrating macrophages and neutrophils in WT was prevented in miR-155 KO mice. Kupffer cells isolated from miR-155 KO mice exhibited predominance of M2 phenotype when exposed to M1 polarized signals and this was due to increased C/EBPβ. Profibrotic genes were attenuated in miR-155 KO mice after alcohol diet or CCl4 treatment. Compared to WT attenuation in CCl4 induced hydroxyproline and α SMA was observed in KO mice. Finally, we show TLR4 signaling regulates miR-155 as TLR4 KO mice showed no induction of miR-155 after alcohol diet. Conclusions Collectively our results demonstrated the role of miR-155 in alcohol-induced steatohepatitis and fibrosis in vivo.

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MiR-214 Promotes the Alcohol-Induced Oxidative Stress via Down-Regulation of Glutathione Reductase and Cytochrome P450 Oxidoreductase in Liver Cells

Abstract: These findings demonstrated a new mechanism by which the alcohol repressed the GSR and POR expression via up-regulation of miR-214 and in turn induced oxidative stress in liver cells.

Cited by 72 publications

References 38 publications

MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

MicroRNA-mediated regulation of glutathione and methionine metabolism and its relevance for liver disease

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

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