Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell
Activation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis, characterized by dramatic disappearance of lipid droplets (LDs). Although LD disappearance has long been considered one of the hallmarks of HSC activation, the underlying molecular mechanisms are largely unknown. In th...
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doaj-b5f1befbc5d04c64bb34c47aaeb62eaf2020-11-25T01:42:17ZengElsevierRedox Biology2213-23172017-04-0111322334Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cellZili Zhang0Shifeng Zhao1Zhen Yao2Ling Wang3Jiangjuan Shao4Anping Chen5Feng Zhang6Shizhong Zheng7Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR ChinaDepartment of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR ChinaDepartment of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR ChinaDepartment of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR ChinaDepartment of Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR ChinaDepartment of Pathology, School of Medicine, Saint Louis University, St Louis., MO 63104, USADepartment of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR ChinaDepartment of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, PR China; Corresponding author at: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR ChinaActivation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis, characterized by dramatic disappearance of lipid droplets (LDs). Although LD disappearance has long been considered one of the hallmarks of HSC activation, the underlying molecular mechanisms are largely unknown. In this study, we sought to investigate the role of autophagy in the process of LD disappearance, and to further examine the underlying mechanisms in this molecular context. We found that LD disappearance during HSC activation was associated with a coordinate increase in autophagy. Inhibition or depletion of autophagy by Atg5 siRNA impaired LD disappearance of quiescent HSCs, and also restored lipocyte phenotype of activated HSCs. In contrast, induction of autophagy by Atg5 plasmid accelerated LD loss of quiescent HSCs. Importantly, our study also identified a crucial role for reactive oxygen species (ROS) in the facilitation of autophagy activation. Antioxidants, such as glutathione and N-acetyl cysteine, significantly abrogated ROS production, and in turn, prevented autophagosome generation and autophagic flux during HSC activation. Besides, we found that HSC activation triggered Rab25 overexpression, and promoted the combination of Rab25 and PI3KCIII, which direct autophagy to recognize, wrap and degrade LDs. Down-regulation of Rab25 activity, using Rab25 siRNA, blocked the target recognition of autophagy on LDs, and inhibited LD disappearance of quiescent HSCs. Moreover, the scavenging of excessive ROS could disrupt the interaction between autophagy and Rab25, and increase intracellular lipid content. Overall, these results provide novel implications to reveal the molecular mechanism of LD disappearance during HSC activation, and also identify ROS-Rab25-dependent autophagy as a potential target for the treatment of liver fibrosis. Keywords: Autophagy, Lipid droplets, Hepatic stellate cells, ROS, Rab25http://www.sciencedirect.com/science/article/pii/S2213231716303093 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zili Zhang Shifeng Zhao Zhen Yao Ling Wang Jiangjuan Shao Anping Chen Feng Zhang Shizhong Zheng |
spellingShingle |
Zili Zhang Shifeng Zhao Zhen Yao Ling Wang Jiangjuan Shao Anping Chen Feng Zhang Shizhong Zheng Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell Redox Biology |
author_facet |
Zili Zhang Shifeng Zhao Zhen Yao Ling Wang Jiangjuan Shao Anping Chen Feng Zhang Shizhong Zheng |
author_sort |
Zili Zhang |
title |
Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell |
title_short |
Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell |
title_full |
Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell |
title_fullStr |
Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell |
title_full_unstemmed |
Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell |
title_sort |
autophagy regulates turnover of lipid droplets via ros-dependent rab25 activation in hepatic stellate cell |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2017-04-01 |
description |
Activation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis, characterized by dramatic disappearance of lipid droplets (LDs). Although LD disappearance has long been considered one of the hallmarks of HSC activation, the underlying molecular mechanisms are largely unknown. In this study, we sought to investigate the role of autophagy in the process of LD disappearance, and to further examine the underlying mechanisms in this molecular context. We found that LD disappearance during HSC activation was associated with a coordinate increase in autophagy. Inhibition or depletion of autophagy by Atg5 siRNA impaired LD disappearance of quiescent HSCs, and also restored lipocyte phenotype of activated HSCs. In contrast, induction of autophagy by Atg5 plasmid accelerated LD loss of quiescent HSCs. Importantly, our study also identified a crucial role for reactive oxygen species (ROS) in the facilitation of autophagy activation. Antioxidants, such as glutathione and N-acetyl cysteine, significantly abrogated ROS production, and in turn, prevented autophagosome generation and autophagic flux during HSC activation. Besides, we found that HSC activation triggered Rab25 overexpression, and promoted the combination of Rab25 and PI3KCIII, which direct autophagy to recognize, wrap and degrade LDs. Down-regulation of Rab25 activity, using Rab25 siRNA, blocked the target recognition of autophagy on LDs, and inhibited LD disappearance of quiescent HSCs. Moreover, the scavenging of excessive ROS could disrupt the interaction between autophagy and Rab25, and increase intracellular lipid content. Overall, these results provide novel implications to reveal the molecular mechanism of LD disappearance during HSC activation, and also identify ROS-Rab25-dependent autophagy as a potential target for the treatment of liver fibrosis. Keywords: Autophagy, Lipid droplets, Hepatic stellate cells, ROS, Rab25 |
url |
http://www.sciencedirect.com/science/article/pii/S2213231716303093 |
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