Augmenter of liver regeneration protects against carbon tetrachloride-induced liver injury by promoting the autophagy in mice

Han, Wei; Shi, Huidong; Duan, Zhijian

doi:10.1016/s0168-8278(17)31003-6

Cited by 6 publications

(7 citation statements)

References 27 publications

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“…F). CCl 4 ‐induced fibrosis increased LC3‐II and decreased LC3‐I in liver tissues, as reported previously . SPD treatment promoted autophagy and further increased LC3‐II levels in both WT and Nrf2 ‐/‐ mice, but not p62 ‐/‐ and Nrf2 ‐/‐ ;p62 ‐/‐ mice.…”

Section: Resultssupporting

confidence: 86%

Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S‐Mediated Noncanonical Mechanism

et al. 2019

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Spermidine (SPD), a naturally occurring polyamine, has been recognized as a caloric restriction mimetic that confers health benefits, presumably by inducing autophagy. Recent studies have reported that oral administration of SPD protects against liver fibrosis and hepatocarcinogenesis through activation of microtubule associated protein 1S (MAP1S)–mediated autophagy. Nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) is a transcription factor that mediates cellular protection by maintaining the cell's redox, metabolic, and proteostatic balance. In this study, we demonstrate that SPD is a noncanonical NRF2 inducer, and that MAP1S is a component of this noncanonical pathway of NRF2 activation. Mechanistically, MAP1S induces NRF2 signaling through two parallel mechanisms, both resulting in NRF2 stabilization: (1) MAP1S competes with Kelch‐like ECH‐associated protein 1 (KEAP1) for NRF2 binding through an ETGE motif, and (2) MAP1S accelerates p62‐dependent degradation of KEAP1 by the autophagy pathway. We further demonstrate that SPD confers liver protection by enhancing NRF2 signaling. The importance of both NRF2 and p62‐dependent autophagy in SPD‐mediated liver protection was confirmed using a carbon tetrachloride–induced liver fibrosis model in wild‐type, Nrf2‐/‐, p62‐/‐ and Nrf2‐/‐;p62‐/‐ mice, as the protective effect of SPD was significantly reduced in NRF2 or p62 single knockout mice, and completely abolished in the double knockout mice. Conclusion: Our results demonstrate the pivotal role of NRF2 in mediating the health benefit of SPD, particularly in the context of liver pathologies.

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Section: Resultssupporting

confidence: 86%

Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S‐Mediated Noncanonical Mechanism

et al. 2019

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“…This result is consistent with the previous works 20,28 . Our observation is also in line with the fact that the large production of reactive oxygen species (ROS) induced by CCl 4 metabolism in the liver, could induce the autophagy process in HSCs 24,29 …”

Section: Discussionsupporting

confidence: 93%

“…During the activation process, HSCs increase the expression of α‐sma marker and up‐regulate ECM synthesis predominantly by producing collagen type I; the increased proliferative ability is instead determined by the ki67 marker 24–26 . In this work, we show that in CCl 4 treated animals, CQ reduces the expression of both α‐sma and collagen I and down‐regulates the mRNA level of the proliferation marker ki67.…”

Section: Discussionmentioning

confidence: 56%

Effects of autophagy inhibition by chloroquine on hepatic stellate cell activation in CCl₄‐induced acute liver injury mouse model

Lê

Dinh

Dang

et al. 2021

J of Gastro and Hepatol

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Background and Aim Hepatic stellate cells (HSCs) activation, a critical event in liver fibrosis, has been recently shown to be related to autophagy. Determine whether chloroquine (CQ) could affect (i) the activation of HSC in vivo and (ii) the hepatic damage in a mice acute liver injury model. Methods The acute liver injury was induced in BALB/c mice by carbon tetrachloride (CCl4 group); 24 h before and after CCl4 administration animals were treated by CQ (CCl4 + CQ group). As control, mice treated by olive oil were considered. After 48 h from CCl4/olive oil administration, blood samples, liver tissues, and HSCs were harvested for analysis. Results In vivo, CQ attenuates CCl4‐induced acute liver damage as evidenced by (i) the reduction of liver enlargement, (ii) the reduction of liver swelling and necrosis also supported by a certain decrease of circulating transaminases level, and (iii) the reduction of liver fibrosis evaluated by collagen deposition and α‐sma protein expression. In HSCs isolated from CQ treated group, we observed the inhibition of autophagy proved by the increase in p62 protein and the decrease of lc3 protein. In addition, CQ reduced the expression of the HSCs activation markers α‐sma/collagen‐I and down‐regulated the expression of the proliferative marker ki67. Conclusion The autophagy attenuation exerted by CQ together with the reduction of the expression of the proliferation marker in HSCs can lessen the acute liver damage potentially opening the way to novel therapeutic approaches for hepatic fibrosis.

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“…25 Shi et al showed that ALR protected the liver against carbon tetrachlorideinduced liver injury by promoting autophagy in mice. 26 Recently, it was shown that ALR knockdown resulted in the inhibition of DNA synthesis. 27 ALR was shown to promote hepatic regeneration in rat small-for-size liver transplantation.…”

Section: Discussionmentioning

confidence: 99%

Augmenter of liver regeneration enhances cell proliferation through the microRNA‐26a/Akt/cyclin D1 pathway in hepatic cells

Gupta

Sata

Ahamad

et al. 2019

Hepatology Research

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Aim Hepatocytes can proliferate and regenerate when injured by toxins, viral infections, and so on. Augmenter of liver regeneration (ALR) is a key regulator of liver regeneration, but the mechanism is unknown. The role of ALR in other cell types is not known. In the present study, we investigated the relationship between microRNA (miRNA)‐26a and ALR in the Huh7 cell line and adipose tissue‐derived mesenchymal cells from chronic liver disease patients and healthy individuals. Methods Huh7 cells were transfected independently with ALR and miRNA‐26a expression vectors, and their effects on cell proliferation, the expression of miRNA‐26a, and activation of the phosphatase and tensin homolog and Akt signaling pathways were determined. The experiments were repeated on mesenchymal stem cells derived from healthy individuals and chronic liver disease patients to see whether the observations can be replicated in primary cells. Results Overexpression of ALR or miRNA‐26a resulted in an increase of the phosphorylation of Akt and cyclin D1 expression, whereas it resulted in decreased levels of p‐GSK‐3β and phosphatase and tensin homolog in Huh7 cells. The inhibition of ALR expression by ALR siRNA or anti‐miR‐26a decreased the Akt/cyclin D1 signaling pathway, leading to decreased proliferation. Mesenchymal stem cells isolated from the chronic liver disease patients had a higher ALR expression, while the mesenchymal stem cells isolated from healthy volunteers responded to the growth factor treatments for increased ALR expression. It was found that there was a significant increase in miRNA‐26a expression and proliferation. Conclusions These data clearly showed that ALR induced the expression of miRNA‐26a, which downregulated phosphatase and tensin homolog, resulting in an increased p‐Akt/cyclin D1 pathway and enhanced proliferation in hepatic cells.

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Augmenter of liver regeneration protects against carbon tetrachloride-induced liver injury by promoting the autophagy in mice

Cited by 6 publications

References 27 publications

Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S‐Mediated Noncanonical Mechanism

Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S‐Mediated Noncanonical Mechanism

Effects of autophagy inhibition by chloroquine on hepatic stellate cell activation in CCl₄‐induced acute liver injury mouse model

Augmenter of liver regeneration enhances cell proliferation through the microRNA‐26a/Akt/cyclin D1 pathway in hepatic cells

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Augmenter of liver regeneration protects against carbon tetrachloride-induced liver injury by promoting the autophagy in mice

Cited by 6 publications

References 27 publications

Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S‐Mediated Noncanonical Mechanism

Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S‐Mediated Noncanonical Mechanism

Effects of autophagy inhibition by chloroquine on hepatic stellate cell activation in CCl4‐induced acute liver injury mouse model

Augmenter of liver regeneration enhances cell proliferation through the microRNA‐26a/Akt/cyclin D1 pathway in hepatic cells

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Effects of autophagy inhibition by chloroquine on hepatic stellate cell activation in CCl₄‐induced acute liver injury mouse model