Autophagy in Hepatic Fibrosis

Song, Yang; Zhao, Yingying; Wang, Fei; Tao, Ling; Xiao, Junjie; Chen, Yang

doi:10.1155/2014/436242

Cited by 41 publications

(44 citation statements)

References 104 publications

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“…Recent data indicate that autophagy is a regulatory pathway in liver fibrosis, with profibrogenic effects related to a direct contribution of HSCs activation . Autophagy may supply energy for the activation of HSCs by delivering triglyceride and other components in lipid droplets from autophagosomes to lysosomes for degradation . Increased autophagy is observed in mice with liver injury induced by CCl 4 or thioacetamide, and loss of autophagic function by attenuated expression of Atg7 results in a reduction of fibrogenesis .…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride‐induced fibrosis

San‐Miguel

Crespo

Sánchez

et al. 2015

Journal of Pineal Research

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This study aimed to investigate whether inhibition of autophagy and endoplasmic reticulum (ER stress) associates with the antifibrogenic effect of melatonin in mice treated with carbon tetrachloride (CCl4 ). Mice received CCl4 5 μL/g body wt i.p. twice a week for 4 wk or 6 wk. Melatonin was given at 5 or 10 mg/kg/day i.p, beginning 2 wk after the start of CCl4 administration. Treatment with CCl4 resulted in fibrosis evidenced by the staining of α-smooth muscle actin (α-SMA)-positive cells. CCl4 induced an autophagic response measured as the presence of autophagic vesicles, protein 1 light chain 3 (LC3) staining, conversion of LC3-I to autophagosome-associated LC3-II, changes in expression of beclin-1, UV radiation resistance-associated gene (UVRAG), ubiquitin-like autophagy-related (Atg5), Atg12, Atg16L1, sequestosome 1 (p62/SQSTM1), and lysosome-associated membrane protein (LAMP)-2, and increased phosphorylation of the mammalian target of rapamycin (mTOR). There was an increase in the expression of the ER stress chaperones CCAAT/enhancer-binding protein homologous protein (CHOP), immunoglobulin-heavy-chain-binding protein (BiP/GRP78), and 94-kDa glucose-regulated protein (GRP94), and in the mRNA levels of pancreatic ER kinase (PERK), activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1 (IRE1), and spliced X-box-binding protein-1 (XBP1). Phospho-IRE1, ATF6, and phospho-PERK protein concentration also increased significantly. Immunohistochemical staining of α-SMA indicated an abrogation of hepatic stellate cells activation by melatonin. Furthermore, treatment with the indole resulted in significant inhibition of the autophagic flux and the unfolded protein response. Findings from this study give new insight into molecular pathways accounting for the protective effect of melatonin in fibrogenesis.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride‐induced fibrosis

San‐Miguel

Crespo

Sánchez

et al. 2015

Journal of Pineal Research

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“…It has been suggested that autophagy may play a role in the regenerative potential of stem cell therapy939. Jung et al reported that the mechanism by which human placenta-derived MSCs promote tissue regeneration may involve HIF-alpha and autophagy, with autophagy being induced in CCl 4 -damaged hepatic cells in a hypoxia-dependent manner9.…”

Section: Discussionmentioning

confidence: 99%

Tonsil-derived Mesenchymal Stem Cells Ameliorate CCl4–induced Liver Fibrosis in Mice via Autophagy Activation

Park

Kim

Woo

et al. 2015

Sci Rep

101

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Liver transplantation is the treatment of choice for chronic liver failure, although it is complicated by donor shortage, surgery-related complications, and immunological rejection. Cell transplantation is an alternative, minimally invasive treatment option with potentially fewer complications. We used human palatine tonsil as a novel source of mesenchymal stem cells (T-MSCs) and examined their ability to differentiate into hepatocyte-like cells in vivo and in vitro. Carbon tetrachloride (CCl4) mouse model was used to investigate the ability of T-MSCs to home to the site of liver injury. T-MSCs were only detected in the damaged liver, suggesting that they are disease-responsive. Differentiation of T-MSCs into hepatocyte-like cells was confirmed in vitro as determined by expression of hepatocyte markers. Next, we showed resolution of liver fibrosis by T-MSCs via reduction of TGF-β expression and collagen deposition in the liver. We hypothesized that autophagy activation was a possible mechanism for T-MSC-mediated liver recovery. In this report, we demonstrate for the first time that T-MSCs can differentiate into hepatocyte-like cells and ameliorate liver fibrosis via autophagy activation and down-regulation of TGF-β. These findings suggest that T-MSCs could be used as a novel source for stem cell therapy targeting liver diseases.

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“…Along with HSCs activation, autophagy flux is up‐regulated. Autophagy may supply energy for activation of HSCs by delivering triglyceride and other components in lipid drops from autophagosomes to lysosomes for degradation 19, 20. Hernández‐Gea et al .…”

Section: Discussionmentioning

confidence: 99%

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

Shi

Ren

Chen

et al. 2016

J Cellular Molecular Medi

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A previous study has demonstrated that Ganshuang granule (GSG) plays an anti‐fibrotic role partially by deactivation of hepatic stellate cells (HSCs). In HSCs activation, mammalian target of rapamycin (mTOR)‐autophagy plays an important role. We attempted to investigate the role of mTOR‐autophagy in anti‐fibrotic effect of GSG. The cirrhotic mouse model was prepared to demonstrate the anti‐fibrosis effect of GSG. High performance liquid chromatography (HPLC) analyses were used to identify the active component of GSG. The primary mouse HSCs were isolated and naringin was added into activated HSCs to observe its anti‐fibrotic effect. 3‐methyladenine (3‐MA) and Insulin‐like growth factor‐1 (IGF‐1) was added, respectively, into fully activated HSCs to explore the role of autophagy and mTOR. GSG played an anti‐fibrotic role through deactivation of HSCs in cirrhotic mouse model. The concentration of naringin was highest in GSG by HPLC analyses and naringin markedly suppressed HSCs activation in vitro, which suggested that naringin was the main active component of GSG. The deactivation of HSCs caused by naringin was not because of the autophagic activation but mTOR inhibition, which was supported by the following evidence: first, naringin induced autophagic activation, but when autophagy was blocked by 3‐MA, deactivation of HSCs was not attenuated or reversed. Second, naringin inhibited mTOR pathway, meanwhile when mTOR was activated by IGF‐1, deactivation of HSCs was reversed. In conclusion, we have demonstrated naringin in GSG suppressed activation of HSCs for anti‐fibrosis effect by inhibition of mTOR, indicating a potential therapeutic application for liver cirrhosis.

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Autophagy in Hepatic Fibrosis

Cited by 41 publications

References 104 publications

RETRACTED: Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride‐induced fibrosis

RETRACTED: Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride‐induced fibrosis

Tonsil-derived Mesenchymal Stem Cells Ameliorate CCl4–induced Liver Fibrosis in Mice via Autophagy Activation

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

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