Modulation of hepatic stellate cells and reversibility of hepatic fibrosis

Huang, Yu; Deng, Xin; Liang, Jian

doi:10.1016/j.yexcr.2017.02.038

Cited by 94 publications

(79 citation statements)

References 80 publications

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“…Chronic liver disease can progress to advanced fibrosis and cirrhosis, can accompany abnormal liver vascular architecture and functional failure, and can lead to hepatocellular carcinoma (HCC) (2). Significant advances in different cell and organism models have revealed molecular mechanisms that underlie the progression of liver fibrosis (3). Liver fibrosis involves a several-fold increase in the ECM (1).…”

mentioning

confidence: 99%

Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms

et al. 2018

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Fibrosis is characterized by the increased accumulation of extracellular matrix (ECM), which drives abnormal cell proliferation and progressive organ dysfunction in many inflammatory and metabolic diseases. Studies have shown that halofuginone, a racemic halogenated derivative, inhibits glutamyl‐prolyl‐transfer RNA‐synthetase (EPRS)‐mediated fibrosis. However, the mechanism by which this occurs is unclear. We explored the mechanistic aspects of how EPRS could develop liver fibrotic phenotypes in cells and animal models. Treatment with TGF‐β1 up‐regulated fibronectin and collagen I levels in LX2 hepatic stellate cells. This effect was inhibited in prolyl‐transfer RNA synthetase (PRS)‐suppressed LX2 cells. Using the promoter luciferase assay, TGF‐β1–mediated collagen I, α1 chain transcription and γ2 basal laminin transcription in LX2 cells were down‐regulated by EPRS suppression, suggesting that EPRS may play roles in ECM production at transcriptional levels. Furthermore, signal transducer and activator of transcription (STAT) signaling activation was involved in the effects of TGF‐β1 on ECM expression in a PRS‐dependent manner. This was mediated via a protein‐protein complex formation consisting of TGF‐β1 receptor, EPRS, Janus kinases, and STAT6. Additionally, ECM expression in fibrotic livers overlapped with EPRS expression along fibrotic septa regions and was positively correlated with STAT6 activation in carbon tetrachloride‐treated mice. This was less obvious in livers of Eprs−/+ mice. These findings suggest that, during fibrosis development, EPRS plays roles in nontranslational processes of ECM expression via intracellular signaling regulation upon TGF‐β1 stimulation.—Song, D.‐G., Kim, D., Jung, J. W., Nam, S. H., Kim, J. E., Kim, H.‐J., Kim, J. H., Lee, S.‐J., Pan, C.‐H., Kim, S., Lee, J. W. Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms. FASEB J. 33, 4341–4354 (2019). http://www.fasebj.org

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confidence: 99%

Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms

et al. 2018

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“…Activated HSCs exhibit a myofibroblast-like phenotype with positive α-SMA expression and excessive collagen secretion [2]. Among the central events, TGF-β1 is a key mediator that has been given considerable attention by a sizable number of research scientists.…”

Section: Discussionmentioning

confidence: 99%

“…When activated, HSCs assume myofibroblast phenotype, resulting in rapid proliferation and massive collagen synthesis with attendant excessive extracellular matrix deposition. The collagen deposition could be degraded, thereby reversing the processes leading to the development of fibrosis, as evidenced in recent studies [2]. However, there is as at now no available therapeutic modality for preventing and/or effectively managing this condition.…”

Section: Introductionmentioning

confidence: 99%

Mitigation of TGF-β/Smad signaling pathway-associated liver fibrosis by paeoniflorin

Li¹,

Wei²

2017

Trop. J. Pharm Res

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“…Hepatic fibrosis is an exacerbated wound-healing response with excessive synthesis and deposition of extracellular matrix (ECM) in the liver [157]. The ECM components are synthesized by hepatic stellate cells (HSC) [158]. For this reason, excessive HSC activation is believed to be the main cause of the hepatic fibrotic process and maintenance.…”

Section: Ironmentioning

confidence: 99%

Trace Elements, PPARs, and Metabolic Syndrome

Shi

Zou

Shen

et al. 2020

IJMS

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Metabolic syndrome (MetS) is a constellation of metabolic derangements, including central obesity, insulin resistance, hypertension, glucose intolerance, and dyslipidemia. The pathogenesis of MetS has been intensively studied, and now many factors are recognized to contribute to the development of MetS. Among these, trace elements influence the structure of proteins, enzymes, and complex carbohydrates, and thus an imbalance in trace elements is an independent risk factor for MetS. The molecular link between trace elements and metabolic homeostasis has been established, and peroxisome proliferator-activated receptors (PPARs) have appeared as key regulators bridging these two elements. This is because on one hand, PPARs are actively involved in various metabolic processes, such as abdominal adiposity and insulin sensitivity, and on the other hand, PPARs sensitively respond to changes in trace elements. For example, an iron overload attenuates hepatic mRNA expression of Ppar-α; zinc supplementation is considered to recover the DNA-binding activity of PPAR-α, which is impaired in steatotic mouse liver; selenium administration downregulates mRNA expression of Ppar-γ, thereby improving lipid metabolism and oxidative status in the liver of high-fat diet (HFD)-fed mice. More importantly, PPARs' expression and activity are under the control of the circadian clock and show a robust 24 h rhythmicity, which might be the reasons for the side effects and the clinical limitations of trace elements targeting PPARs. Taken together, understanding the casual relationships among trace elements, PPARs' actions, and the pathogenesis of MetS is of great importance. Further studies are required to explore the chronopharmacological effects of trace elements on the diurnal oscillation of PPARs and the consequent development of MetS.

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Modulation of hepatic stellate cells and reversibility of hepatic fibrosis

Cited by 94 publications

References 80 publications

Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms

Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms

Mitigation of TGF-β/Smad signaling pathway-associated liver fibrosis by paeoniflorin

Trace Elements, PPARs, and Metabolic Syndrome

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