Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression

Heo, Mi Jeong; Kim, Tae Hyun; You, Jueng Soo; Blaya, Delia; Sancho‐Bru, Pau

doi:10.1136/gutjnl-2017-315123

Cited by 214 publications

(170 citation statements)

References 51 publications

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“…The NLRP3activating factor TXNIP is inhibited by several individual miRNAs. Expression levels of miR-17-5p in rat brains and rat insulin-producing cells with endoplasmic reticulum stress (76,77), of miR-20a-5p in rat fibroblast-like synoviocytes in adjuvantinduced arthritis (78), and of miR-148a-3p in mouse hepatocytes in alcoholic hepatitis (79) are decreased and correlate with upregulation of TXNIP and activation of the NLRP3 inflammasome. Upregulation of the miRNAs with mimics reversed these effects.…”

Section: Mirnas Modulate Inflammasome Regulationmentioning

confidence: 99%

Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases

Boxberger

Hecker

Zettl

2019

The Journal of Immunology

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Inflammasomes are protein complexes that respond to a wide range of pathogens and cellular damage signals. Their activation prompts the caspase-1–mediated cleavage of the proinflammatory cytokines IL-1β and IL-18. Inflammasome dysregulation has been demonstrated to play a role in a range of diseases involving the adaptive immune system like multiple sclerosis, rheumatic diseases, and type 1 diabetes. Priming and activation of inflammasomes can be modulated by microRNAs (miRNAs), small noncoding RNAs that regulate gene expression posttranscriptionally. miRNAs, such as miR-223-3p, have been demonstrated to directly target the inflammasome components NLRP3, caspase-1, and caspase-8. Other miRNAs like miR-155-5p modulate TLR-, IL-1R–, TNFR-, and IFNAR-mediated signaling pathways upstream of the inflammasomes. In this study, we discuss how a more detailed elucidation of miRNA-driven inflammasome regulation helps in understanding the molecular processes underlying immune-mediated human diseases, holds potential for the identification of biomarkers and may offer novel targets for the development of future therapeutics.

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Section: Mirnas Modulate Inflammasome Regulationmentioning

confidence: 99%

Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases

Boxberger

Hecker

Zettl

2019

The Journal of Immunology

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“…41,42 Recently, a new regulatory mechanism of the thioredoxin-interacting protein (TXNIP)/ NLRP3 pathway in response to ethanol was described. 43 Using Lieber-DeCarli alcohol feeding and a binge alcoholdrinking model, the authors were able to identify a dosedependent alleviation of microribonucleic acid miR-148a in ASH mice, which in turn promotes the overexpression of thioredoxin and the activation of the NLRP3 inflammasome. Genes of NLRP3, ASC, and IL-1β were transcriptionally upregulated in both ethanol-induced ASH models compared with controls.…”

Section: Nlrp3 In Alcoholic Steatohepatitis In Micementioning

confidence: 99%

The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis

et al. 2020

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Nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis (ASH) are advanced forms of fatty liver diseases that are associated with a high morbidity and mortality worldwide. Patients with ASH or NASH are more susceptible to the progression of fibrosis and cirrhosis up to the development of hepatocellular carcinoma. Currently, there are limited medical therapies available. Accompanied by the asymptomatic disease progression, the demand for liver transplants is high. This review provides an overview about the growing evidence for a central role of NLR family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex that acts as a central driver of inflammation via activation of caspase 1, maturation and release of pro-inflammatory cytokines including interleukin-1β, and trigger of inflammatory pyroptotic cell death in both NASH and ASH. We also discuss potential therapeutic approaches targeting NLRP3 inflammasome and related upstream and downstream pathways to develop prognostic biomarkers and medical treatments for both liver diseases.

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“…FoxO1 (Heo et al, 2018). Finally, ethanol downregulates pri-miR-122 expression by upregulating the spliced form of GRHL2 (Satishchandran et al, 2018).…”

Section: Alcohol Also Reduces Mir-148a Expression In Hepatocytes By Imentioning

confidence: 99%

Noncoding RNAs in alcoholic liver disease

Chen

et al. 2019

Journal Cellular Physiology

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Alcoholic liver disease (ALD) is a complex process with high morbitity and can cause liver dysfunction, which contains a wide spectrum of hepatic lesions, including steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. To date, the molecular mechanisms for ALD have not been fully explored and an effective therapy is still missing. Overwhelming evidence shows dysregulation of noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs), is correlated with etiopathogenesis and progress of ALD including hepatocyte damage, disrupted lipid metabolism, aggressive inflammatory responses, oxidative stress, programmed cell death, fibrosis, and epigenetic changes induced by alcohol. For example, circulating miRNA‐122 is a marker of hepatocyte damage, and miRNA‐155 is a potential marker of inflammation, indicating their diagnosis therapeutic potential in ALD. In addition, roles for long noncoding RNAs (lncRNAs) and circular RNAs in ALD are being uncovered. Further, circulating ncRNAs and exosome‐derived ncRNAs have attracted more attention lately, suggesting a role in the prevention and treatment of ALD. This review covers the roles of ncRNAs in ALD, and the potential uses as markers for diagnosis and therapeutic options.

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Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression

Abstract: Alcohol decreases miR-148a expression in hepatocytes through FoxO1, facilitating TXNIP overexpression and NLRP3 inflammasome activation, which induces hepatocyte pyroptosis. Our findings provide information on novel targets for reducing incidence and progression of ALD.

Cited by 214 publications

References 51 publications

Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases

Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases

The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis

Noncoding RNAs in alcoholic liver disease

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