<scp>MiR</scp>‐146b attenuates high‐fat diet‐induced non‐alcoholic steatohepatitis in mice

Jiang, Weiwei; Liu, Juan; Dai, Yulin; Zhou, Nan; Ji, Chenling; Li, Xiaonan

doi:10.1111/jgh.12878

Cited by 36 publications

(39 citation statements)

References 31 publications

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“…It is, however, well possible that under physiological conditions a single miRNA plays only a role in fine modulation of complex signaling networks. It would therefore be interesting to test whether exogenous administration of miR‐146b‐5p could have beneficial effects in diseases involving IL‐6, as shown in high‐fat diet‐induced non‐alcoholic steatohepatitis in rats …”

Section: Discussionmentioning

confidence: 99%

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Kirchmeyer

Servais

Hamdorf

et al. 2018

Journal of Leukocyte Biology

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Interleukin-6 (IL-6)-type cytokines play important roles in liver (patho-)biology. For instance, they regulate the acute phase response to inflammatory signals and are involved in hepatocarcinogenesis. Much is known about the regulation of protein-coding genes by cytokines whereas their effects on the miRNome is less well understood. We performed a microarray screen to identify microRNAs (miRNAs) in human hepatocytes which are modulated by IL-6-type cytokines. Using samples of 2 donors, 27 and 68 miRNAs (out of 1,733) were found to be differentially expressed upon stimulation with hyper-IL-6 (HIL-6) for up to 72 h, with an overlap of 15 commonly regulated miRNAs. qPCR validation revealed that miR-146b-5p was also consistently up-regulated in hepatocytes derived from 2 other donors. Interestingly, miR-146b-5p (but not miR-146a-5p) was induced by IL-6-type cytokines (HIL-6 and OSM) in non-transformed liver-derived PH5CH8 and THLE2 cells and in Huh-7 hepatoma cells, but not in HepG2 or Hep3B hepatoma cells. We did not find evidence for a differential regulation of miR-146b-5p expression by promoter methylation, also when analyzing the TCGA data set on liver cancer samples. Inducible overexpression of miR-146b-5p in PH5CH8 cells followed by RNA-Seq analysis revealed effects on multiple mRNAs, including those encoding IRAK1 and TRAF6 crucial for Toll-like receptor signaling. Indeed, LPSmediated signaling was attenuated upon overexpression of miR-146b-5p, suggesting a regulatory loop to modulate inflammatory signaling in hepatocytes. Further validation experiments suggest DNAJC6, MAGEE1, MPHOSPH6, PPP2R1B, SLC10A3, SNRNP27, and TIMM17B to be novel targets for miR-146b-5p (and miR-146a-5p). K E Y W O R D Shepatocarcinogenesis, IL-6-type cytokines, liver, microRNAs, miR-146a-5p steatohepatitis; NF B, nuclear factor kappaB; OSM, oncostatin M; PPP2R1B, protein phosphatase 2 scaffold subunit Abeta; pre-miRNA, precursor-miRNA; pri-miRNA, primary-miRNA; SRPRB, SRP receptor beta subunit; STAT, signal transducer and activator of transcription; TNF , tumor necrosis factor alpha; TRAF6, TNF receptor associated factor 6; TSS, transcription starting site This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Kirchmeyer

Servais

Hamdorf

et al. 2018

Journal of Leukocyte Biology

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“…As a pivotal adaptor orchestrating inflammation, TRAF6 has emerged as an attractive drug target for several diseases, especially cancer . In terms of NAFLD, TRAF6 inactivation is responsible for the miR‐146b–mediated attenuation of steatohepatitis . TRAF6 also participates in obesity‐associated insulin resistance by transducing the CD40 signaling pathway .…”

Section: Discussionmentioning

confidence: 99%

“…(27,28) In terms of NAFLD, TRAF6 inactivation is responsible for the miR-146bmediated attenuation of steatohepatitis. (29) TRAF6 also participates in obesity-associated insulin resistance by transducing the CD40 signaling pathway. (30) Here, we report that blocking TRAF6 ubiquitination to inactivate downstream MAPK and NF-jB signaling largely explained the inhibitory effect of LILRB4 on NAFLD progression, thereby providing further support for developing TRAF6 and its ubiquitination activation as therapeutic targets for inflammation-related pathologies.…”

Section: Discussionmentioning

confidence: 99%

Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway

Jiang

Dai

et al. 2018

Hepatology

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Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver pathology characterized by hepatic steatosis and commonly accompanied by systematic inflammation and metabolic disorder. Despite an accumulating number of studies, no pharmacological strategy is available to treat this condition in the clinic. In this study, we applied extensive gain‐ and loss‐of‐function approaches to identify the key immune factor leukocyte immunoglobulin‐like receptor B4 (LILRB4) as a negative regulator of NAFLD. The hepatocyte‐specific knockout of LILRB4 (LILRB4‐HKO) exacerbated high‐fat diet–induced insulin resistance, glucose metabolic imbalance, hepatic lipid accumulation, and systematic inflammation in mice, whereas LILRB4 overexpression in hepatocytes showed a completely opposite phenotype relative to that of LILRB4‐HKO mice when compared with their corresponding controls. Further investigations of molecular mechanisms demonstrated that LILRB4 recruits SHP1 to inhibit TRAF6 ubiquitination and subsequent inactivation of nuclear factor kappa B and mitogen‐activated protein kinase cascades. From a therapeutic perspective, the overexpression of LILRB4 in a genetic model of NAFLD, ob/ob mice, largely reversed the inherent hepatic steatosis, inflammation, and metabolic disorder. Conclusion: Targeting hepatic LILRB4 to improve its expression or activation represents a promising strategy for the treatment of NAFLD as well as related liver and metabolic diseases. (Hepatology 2018;67:1303‐1319)

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“…The overexpression of miR‐451 significantly decreases inflammatory cytokines via the AMPK/AKT pathway . The administration of miR‐146b decreases TRAF6 , interleukin (IL)‐1 receptor‐associated kinase 1 ( IRAK1 ), TNF‐α and IL‐6 in vitro and in vivo , which downregulates the downstream molecules (nuclear factor kappa‐light‐chain‐enhancer of activated B cells [NF‐κB]) and finally ameliorates HFD‐induced NASH . Decreased miR‐144 can upregulate the TNF‐α and interferon (IFN)‐γ levels via binding to 3′‐UTR of TLR2 mRNA.…”

Section: Mirnas Involved In the Pathogenesis Of Nafldmentioning

confidence: 99%

“…73 The administration of miR-146b decreases TRAF6, interleukin (IL)-1 receptor-associated kinase 1 (IRAK1), TNF-α and IL-6 in vitro and in vivo, which downregulates the downstream molecules (nuclear factor kappa-lightchain-enhancer of activated B cells [NF-κB]) and finally ameliorates HFD-induced NASH. 74 Decreased miR-144 can upregulate the TNF-α and interferon (IFN)-γ levels via binding to 3′-UTR of TLR2 mRNA. The miR-144 inhibitor can increase the expressions of TLR2, TNF-α, Journal of Digestive Diseases 2016; 17; 708-715 IFN-γ and the activation of NF-κB, suggesting that it might serve as a potential target for NASH therapy.…”

Section: Mirnas In Hepatic Inflammation and Fibrosismentioning

confidence: 99%

MicroRNAs as biomarkers and regulators of nonalcoholic fatty liver disease

Liu

Cao

Fan

2016

J of Digest Diseases

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Nonalcoholic fatty liver disease (NAFLD) is a complicated disease affected by the interaction of environmental and genetic factors; however, the precise pathogenesis of the disease has not been fully determined. There is a need to better understand the pathogenesis of NAFLD and to identify non-invasive diagnostic modalities. Recent advances in systematic biology and epigenetics have improved our understanding of the genotype-phenotype relationships in NAFLD. MicroRNAs (miRNAs) are important regulators of a wide range of biological processes. MiRNAs are extremely stable and protect from RNAase-mediated degradation in body fluids, making them attractive candidate biomarkers for the early detection of the disease and the monitoring of disease progression. In this review, we summarized the current knowledge on miRNAs as potential biomarkers of NAFLD at different stages and for the prognosis of advanced diseases. Furthermore, we discussed the implications of miRNAs that functioning in lipid metabolism and hepatic steatosis as well as in hepatic inflammation and fibrosis with regard to the pathogenesis of NAFLD.

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MiR‐146b attenuates high‐fat diet‐induced non‐alcoholic steatohepatitis in mice

Abstract: MiR-146b ameliorated HFD-induced NASH by directly suppressing IRAK1 and TRAF6.

Cited by 36 publications

References 31 publications

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway

MicroRNAs as biomarkers and regulators of nonalcoholic fatty liver disease

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