MicroRNA-200a controls Nrf2 activation by target Keap1 in hepatic stellate cell proliferation and fibrosis

Yang, Jingjing; Tao, Hui; Hu, Wei; Liu, Liping; Shi, Kai-Hu; Deng, Zhiping; Li, Jun

doi:10.1016/j.cellsig.2014.07.016

Cited by 82 publications

(53 citation statements)

References 26 publications

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“…Yang et al demonstrated that miR-200a down-regulates Keap1 and ultimately results in Nrf2-dependent antioxidant pathways active in HSCs. miR200a also decreased TGF-β induced α-SMA expression in HSCs (111).…”

Section: Mir-200amentioning

confidence: 98%

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Kumar

Mahato

2014

Pharm Res

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Liver fibrosis is a pathological condition originating from liver damage that leads to excess accumulation of extracellular matrix (ECM) proteins in the liver. Viral infection, chronic injury, local inflammatory responses and oxidative stress are the major factors contributing to the onset and progression of liver fibrosis. Multiple cell types and various growth factors and inflammatory cytokines are involved in the induction and progression of this disease. Various strategies currently being tried to attenuate liver fibrosis include the inhibition of HSC activation or induction of their apoptosis, reduction of collagen production and deposition, decrease in inflammation, and liver transplantation. Liver fibrosis treatment approaches are mainly based on small drug molecules, antibodies, oligonucleotides (ODNs), siRNA and miRNAs. MicroRNAs (miRNA or miR) are endogenous noncoding RNA of ~22 nucleotides that regulate gene expression at post transcription level. There are several miRNAs having aberrant expressions and play a key role in the pathogenesis of liver fibrosis. Single miRNA can target multiple mRNAs, and we can predict its targets based on seed region pairing, thermodynamic stability of pairing and species conservation. For in vivo delivery, we need some additional chemical modification in their structure, and suitable delivery systems like micelles, liposomes and conjugation with targeting or stabilizing the moiety. Here, we discuss the role of miRNAs in fibrogenesis and current approaches of utilizing these miRNAs for treating liver fibrosis.

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Section: Mir-200amentioning

confidence: 98%

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Kumar

Mahato

2014

Pharm Res

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“…The latter might play a critical role in maintaining Nrf2 pathway activation for an extended period of time, which is beneficial for tissue repair since It is well established that Keap1 regulates the Nrf2 signaling pathway, but the regulation of Keap1 itself is less well documented. Recent studies showed that Keap1 is subjected to posttranscription regulation: its mRNA level was affected by microRNA 200a through its 3= untranslated region (32,33). Another study reported that Keap1 overexpression in HepG2 cells inhibits Nrf2 activity (34).…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

Yin

Cao

2015

Molecular and Cellular Biology

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Toll-like receptors (TLRs) induce inflammation and tissue repair through multiple signaling pathways. The Nrf2 pathway plays a key role in defending against the tissue damage incurred by microbial infection or inflammation-associated diseases. The critical event that mediates TLR-induced Nrf2 activation is still poorly understood. In this study, we found that lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists activate Nrf2 signaling and the activation is due to the reduction of Keap1, the key Nrf2 inhibitor. TLR signaling-induced Keap1 reduction promoted Nrf2 translocation from the cytoplasm to the nucleus, where it activated transcription of its target genes. TLR agonists modulated Keap1 at the protein posttranslation level through autophagy. TLR signaling increased the expression of autophagy protein p62 and LC3-II and induced their association with Keap1 in the autophagosome-like structures. We also characterized the interaction between p62 and Keap1 and found that p62 is indispensable for TLR-mediated Keap1 reduction: TLR signaling had no effect on Keap1 if cells lacked p62 or if cells expressed a mutant Keap1 that could not interact with p62. Our study indicates that p62-mediated Keap1 degradation through autophagy represents a critical linkage for TLR signaling regulation of the major defense network, the Nrf2 signaling pathway.

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“…93,97 In addition, miRNAs are also known to target other Nrf2 regulators and alter Nrf2 activation. 98 Although age-related changes in the expression of miRNAs have been reported, 97 investigating their role in regulating Nrf2 activation and downstream transcriptional responses in cellular/animal models of aging requires further investigation.…”

Section: Keap1-independent Mechanismsmentioning

confidence: 99%

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

Swamy

Rajasekaran

Thannickal

2016

The American Journal of Pathology

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Aging and age-related diseases have been associated with elevated oxidative stress, which may be related to increased production of reactive species and/or a deficiency in antioxidant defenses. The nuclear factor-erythroid-2erelated factor 2 (Nrf2)-mediated antioxidant response pathway maintains cellular reduction-oxidation homeostasis by inducing the transcription of an array of cytoprotective genes. However, there is evidence of impaired Nrf2 response in aging contributing to age-related fibrotic diseases. Herein, we review mechanisms for the dysregulation of Nrf2 signaling in aging. This understanding will pave the way for the design of novel therapeutic strategies that restore Nrf2 signaling to reestablish cellular homeostasis in aging and age-related fibrotic diseases.

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MicroRNA-200a controls Nrf2 activation by target Keap1 in hepatic stellate cell proliferation and fibrosis

Cited by 82 publications

References 26 publications

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

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