Activation of autophagy through calcium‐dependent <scp>AMPK</scp>/<scp>mTOR</scp> and <scp>PKC</scp>θ pathway causes activation of rat hepatic stellate cells under hypoxic stress

Jin, Yuepeng; Bai, Yongyu; Ni, Hong-Bo; Li, Qiang; Ye, Lechi; Shan, Yunfeng; Zhou, Mengtao

doi:10.1002/1873-3468.12090

Cited by 43 publications

(34 citation statements)

References 45 publications

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“…Jin et al . found that activation of autophagy causes activation of rat HSCs through calcium‐dependent AMPK/mTOR and PKCθ pathway under hypoxic stress 7. So we speculated that mTOR‐autophagy pathway may act as an important role in anti‐fibrosis effect of GSG.…”

Section: Introductionmentioning

confidence: 85%

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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Section: Introductionmentioning

confidence: 85%

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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“…mTOR is a highly conserved Ser/Thr protein kinase that forms part of two protein complexes known as mTORC1 and mTORC2. The inactivation of mTORC1 contributes to upregulating autophagy in response to nutrient deprivation or energy deficits, and recent studies have shown that mTORC1 can act as a downstream effector of the AMPK pathway in the regulation of autophagy . Having demonstrated that AMPK is an important regulator in modulating cardiomyocytes autophagy upon changed pHe, we wondered whether mTORC1 participated in the pHe‐meditated regulation of autophagy.…”

Section: Discussionmentioning

confidence: 99%

Extracellular pH regulates autophagy via the AMPK–ULK1 pathway in rat cardiomyocytes

et al. 2016

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Various pathological conditions contribute to pH fluctuations and affect the functions of vital organs such as the heart. In this study, we show that in rat cardiomyocytes, acidic extracellular pH (pHe) inhibits autophagy, whereas alkaline pHe stimulates it. We also find that adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and Unc-51-like kinase 1 (ULK1) are very sensitive to pHe changes. Furthermore, by interfering with AMPK, mTOR or ULK1 activity, we demonstrate that the AMPK-ULK1 pathway, but not the mTOR pathway, plays a crucial role on pHe-regulated autophagy and cardiomyocyte viability. These data provide a potential therapeutic strategy against cardiomyocyte injury triggered by pH fluctuations.

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“…Autophagy has been found induced in the carbon tetrachloride (CCl 4 )‐induced cirrhosis model mice . Furthermore, activation of autophagy causes HSCs activation . Our previous study demonstrated that inhibition of autophagy reversed alcohol‐induced HSCs activation and alleviated alcoholic fatty liver injury in ALF model mice …”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA XIST enhances ethanol‐induced hepatic stellate cells autophagy and activation via miR‐29b/HMGB1 axis

et al. 2019

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Activation of hepatic stellate cells (HSCs) is a prominent driver of liver fibrogenesis, including alcoholic liver fibrosis (ALF). Furthermore, autophagy contributes to HSCs activation. This study aims to investigate the role and the mechanisms of long noncoding RNA XIST in regulating HSCs autophagy and activation. Human HSC cells (LX-2) were treated with 100 mmol/L ethanol to mimic HSCs activation. The HSCs activation was evaluated by determining cell viability and protein levels of fibrosis markers α-smooth muscle actin (α-SMA) and collagen type 1 α1 (CoL1A1). The autophagy was evaluated by measuring autophagy markers Beclin-1 and LC3-II. The interaction among XIST, miR-29b, and high-mobility group box-1 (HMGB1) were analyzed using luciferase reporter assay, qRT-PCR, and western blot. Lentiviruses targeting sh-XIST (LV-sh-XIST) were injected into ALF model mice via tail vein to elucidate the in vivo role of XIST in ALF injury. XIST was upregulated in ethanolactivated LX-2 cells. Furthermore, XIST served as a competitive endogenous RNA of miR-29b to facilitate HMGB1 expression, and thus enhanced ethanol-induced HSCs autophagy and activation. Further in vivo assay showed that downregulation of XIST by LV-sh-XIST alleviated ALF injury in ALF model mice. Collectively, XIST enhances ethanol-induced HSCs autophagy and activation via miR-29b/HMGB1 axis.autophagy, hepatic stellate cells activation, HMGB1, miR-29b, XIST Abbreviations: ALF, alcoholic liver fibrosis; CoL1A1, collagen type 1 α1; ceRNA, competitive endogenous RNA; HMGB, high mobility group protein B1; HMGB1, high-mobility group box-1; HSCs, hepatic stellate cells; HOTAIR, lncRNA HOX transcript antisense RNA; lncRNAs, long noncoding RNAs; LC3-II, microtubule-associated protein 1A/1B-light chain 3; LV-sh-XIST, lentiviruses targeting sh-XIST; LX-2, human HSC cells; MTT, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PF, pulmonary fibrosis; RNA XIST, long noncoding; si-HMGB1, small interfering RNA targeting HMGB1; siRNA, small interfering RNA; si-XIST, small interfering RNA targeting XIST; XIST, LncRNA X-inactive-specific transcript; α-SMA, α-smooth muscle actin.

show abstract

Activation of autophagy through calcium‐dependent AMPK/mTOR and PKCθ pathway causes activation of rat hepatic stellate cells under hypoxic stress

Cited by 43 publications

References 45 publications

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

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

Extracellular pH regulates autophagy via the AMPK–ULK1 pathway in rat cardiomyocytes

Long noncoding RNA XIST enhances ethanol‐induced hepatic stellate cells autophagy and activation via miR‐29b/HMGB1 axis

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