Curcumin raises lipid content by Wnt pathway in hepatic stellate cell

Zhang, Feng; Lu, Chunfeng; Xu, Wenxuan; Wu, Li; Lu, Yin; Zheng, Shizhong

doi:10.1016/j.jss.2015.08.040

Cited by 16 publications

(15 citation statements)

References 31 publications

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“…Agonists of this pathway, roof plate-specific spondin (RSPO) proteins, are involved in HSC activation [120]. Moreover, the induction of Wnt signaling triggers HSC activation and loss of LDs by decreasing expression of RXR, RAR, peroxisome proliferator-activated receptor γ, and CCAAT/enhancer-binding protein α [121].…”

Section: Central Carbon and Nitrogen Metabolismmentioning

confidence: 99%

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Khomich

Ivanov

Bartosch

2019

Cells

162

154

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Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.Most of the progress that has been made in the identification of the molecular mechanisms underlying fibrosis is based on the use of in vitro model systems using tissue culture-adapted HSC lines, primary HSC preparations, and a number of in vivo models such as animals being fed high-fat/cholesterol or choline-deficient diets, animals that undergo bile duct ligation, treatment with ethanol, CCl 4 or other chemical agents, or transgenic animals [5]. Hepatic Stellate CellsThe cell type that is predominantly responsible for fibrotic processes is hepatic stellate cells (HSCs), a mesenchymal cell population that constitutes 5-10% of the total number of cells in the liver (Figure 1). HSCs are located in the perisinusoidal space (space of Disse) and are surrounded by hepatocytes and sinusoidal endothelial cells [6,7]. Their main functions are the secretion of laminin, proteoglycans, and type IV collagen to form basement membrane-like structures. Quiescent HSCs start to proliferate and undergo trans-differentiation into contractile myofibroblasts in response to paracrine stimulation by neighboring cell types, including Kupffer cells, hepatocytes, platelets, leukocytes, and sinusoidal endothelial cells. Kupffer cells can stimulate activation and proliferation of HSCs through the actions of cytokines, and in particular transforming growth factor β1 (TGFβ1), interleukin 1 (IL-1), tumor necrosis factor (TNF), reactive oxygen species (ROS) and lipid peroxides [6,8]. Hepatocytes are an important source of inflammatory lipid peroxides in liver diseases. Platelets release pro-fibrogenic growth factors such as platelet-derived growth factor (PDGF), TGFβ1, and epidermal growth factor (EGF). Neutrophils are an important source of RO...

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Section: Central Carbon and Nitrogen Metabolismmentioning

confidence: 99%

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Khomich

Ivanov

Bartosch

2019

Cells

162

154

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“…Furthermore, Yuen JJ et al also reported that diacylglycerol O-acyltransferase 1 (DGAT1) catalyzed the final step of triglyceride synthesis, transferring an acyl group from acyl-CoA to diacylglycerol, and thus had a role in retinoid storage and metabolism in HSCs [45]. Interestingly, we previously investigated the role of the canonical Wnt/β-catenin pathway in regulation of HSC lipogenesis [11]. In the current study, we evaluated the role of autophagy in the process of LD disappearance, and further examined the underlying mechanisms in this molecular context.…”

Section: Discussionmentioning

confidence: 99%

“…The levels of retinol, triglyceride, and total cholesterol in HSCs were determined by commercially available kits (Nanjing Jiancheng Bioengineering Institute) according to manufacturer's instructions [11].…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies [11], [15], including ours [11], have reported that Diacylglycerol acyltransferase 1 (DGAT1), Adipose triglyceride lipase (ATGL), or Hepatic lipase (LIPC) are all new target molecules, and attract extensive concern of numerous scholars. Moreover, transcriptional regulation is also required to maintain the adipogenic phenotype of HSCs [17], [18], [19].…”

Section: Introductionmentioning

confidence: 93%

“…However, as a consequence of liver injuries, activated HSCs lose their retinols and display a myofibroblastic phenotype accompanied by excessive production of extracellular matrix (ECM), subsequently leading to liver fibrosis [9], [10]. We previously reported that recovering the accumulation of LDs could inhibit the activation of HSCs [11]. The current work was aimed to evaluate the underlying mechanisms of LD disappearance during HSC activation.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell

et al. 2017

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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.

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Curcumin inhibits the activity and induces apoptosis of activated hepatic stellate cell by suppressing autophagy

Shu,

He,

et al. 2023

J of Cellular Biochemistry

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Curcumin, a kind of natural compound, has been previously proven to inhibit the autophagy in hepatic stellate cells (HSCs) and induce their apoptosis. However, it is not clear whether the enhanced apoptosis of activated HSCs (aHSCs) caused by curcumin depends on autophagy inhibition. We aim to verify this hypothesis and explore the potential mechanisms in this study. Immortalized human HSC line LX‐2 was used as an experimental specimen and pretreated with transforming growth factor β1(TGF‐β1) for 24 h to activate it before drug application. The levels of autophagy, apoptosis, cell activity, lipid metabolism, and the activity of the PI3K/Akt/mTOR signal pathway were evaluated by multiple methods, such as Western blotting, mcherry‐EGFP‐LC3B adenoviruses transfection, immunofluorescence, Nile Red staining, flow cytometry among others. Our results showed that rapamycin, an autophagy activator, could partly offset the effects of curcumin on autophagy and apoptosis of LX‐2 cells, while 3‐Methyladenine (3‐MA), an autophagy inhibitor, could enhance these effects. Furthermore, curcumin could promote the activity of the PI3K/Akt/mTOR signal pathway in LX‐2 cells, while PI3K inhibitor could partly offset this effect and increase the autophagy level. Overall, we demonstrated that curcumin could inhibit the activity and promote LX‐2 cells apoptosis by suppressing autophagy by activating the PI3K/Akt/mTOR signal pathway. In addition, lipid recovery and energy deprivation due to autophagy inhibition may be the exact mechanism by which curcumin attenuates the pro‐fibrotic activity of LX‐2.

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Curcumin raises lipid content by Wnt pathway in hepatic stellate cell

Cited by 16 publications

References 31 publications

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell

Curcumin inhibits the activity and induces apoptosis of activated hepatic stellate cell by suppressing autophagy

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