Chloroquine Improved Carbon Tetrachloride-Induced Liver Fibrosis through Its Inhibition of the Activation of Hepatic Stellate Cells: Role of Autophagy

He, Wei; Wang, Bin; Yang, Jing; Yun, Zhong; Wang, Liangzhi; Huang, Xiao-Dan; Chen, Jianping

doi:10.1248/bpb.b14-00297

Cited by 36 publications

(35 citation statements)

References 15 publications

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“…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 . The autophagy inhibitor chloroquine diminishes liver fibrosis in CCl 4 ‐treated mice and reduces the expression of profibrogenic genes in the mouse stellate cell line JS1 . Melatonin inhibition of autophagy has been recently reported to contribute to its protective effects against focal cerebral ischemia or liver ischemia–reperfusion .…”

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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“…Strikingly, four hits were tricyclic antidepressants (TCAs). The screen also identified chloroquine, which has been shown to reduce hepatic fibrosis in vivo 22.…”

Section: Resultsmentioning

confidence: 99%

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells

Chen¹,

Newcomb²,

Zhou³

et al. 2017

Sci Rep

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Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.

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“…The current data agree on those of He et al . [42] who demonstrated that CQ treatment of hepatic stellate cells in an in vivo liver fibrosis model diminished the expression and organization of α-SMA.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of autophagy inhibits the conversion of cardiac fibroblasts to cardiac myofibroblasts

et al. 2016

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The incidence of heart failure with concomitant cardiac fibrosis is very high in developed countries. Fibroblast activation in heart is causal to cardiac fibrosis as they convert to hypersynthetic cardiac myofibroblasts. There is no known treatment for cardiac fibrosis. Myofibroblasts contribute to the inappropriate remodeling of the myocardial interstitium, which leads to reduced cardiac function and ultimately heart failure. Elevated levels of autophagy have been linked to stress-induced ventricular remodeling and other cardiac diseases. Previously, we had shown that TGF-β1 treatment of human atrial fibroblasts both induced autophagy and enhanced the fibrogenic response supporting a linkage between the myofibroblast phenotype and autophagy. We now demonstrate that with in vitro culture of primary rat cardiac fibroblasts, inhibition of autophagy represses fibroblast to myofibroblast phenoconversion. Culturing unpassaged cardiac fibroblasts for 72 hours on plastic tissue culture plates is associated with elevated α-smooth muscle actin (α-SMA) expression. This activation parallels increased microtubule-associated protein 1A/1B-light chain 3 (LC-3β II) protein expression. Inhibition of autophagy with bafilomycin-A1 (Baf-A1) and chloroquine (CQ) in cardiac fibroblasts significantly reduces α-SMA and extracellular domain A fibronectin (ED-A FN) protein vs untreated controls. Myofibroblast cell migration and contractility were significantly reduced following inhibition of autophagy. These data support the possibility of a causal link between cardiac fibroblast-to-myofibroblast phenoconversion and autophagy.

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Chloroquine Improved Carbon Tetrachloride-Induced Liver Fibrosis through Its Inhibition of the Activation of Hepatic Stellate Cells: Role of Autophagy

Cited by 36 publications

References 15 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

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells

Inhibition of autophagy inhibits the conversion of cardiac fibroblasts to cardiac myofibroblasts

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