Activation of hepatic stellate cell in Pten null liver injury model

He, Liyun; Gubbins, James; Peng, Zhechu; Medina, Vivian; Fei, Fan; Asahina, Kinji; Wang, Jiaohong; Kahn, Michaël; Rountree, C. Bart; Stiles, Bangyan L.

doi:10.1186/s13069-016-0045-1

Cited by 39 publications

(50 citation statements)

References 27 publications

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“…1C). Importantly, it is well known that LDs of HSCs mainly contain retinol, triglycerides and cholesterol [5], [6], [7], [8], [9], [10]. Therefore, we detected the level of retinol, triglycerides and cholesterol from quiescent HSCs to activated HSCs, respectively.…”

Section: Resultsmentioning

confidence: 94%

“…3F). Furthermore, main components of LDs, retinol, triglyceride and cholesterol [5], [6], [7], [8], [9], [10], were determined to reveal changes of LD content in activated HSCs. A nearly 1.5-fold increase in retinol, triglyceride and cholesterol content could be evidenced (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Besides, cholesterol, cholesteryl ester, phospholipids and free fatty acids are also reported to be present in rat HSC LDs [5], [6], [7], [8]. However, following liver injury, whether due to chronic alcohol consumption, viral infection, xenobiotic exposure, iron overload or another less common insult, HSCs undergo a process known as activation, which is a transition of quiescent cells into proliferative, fibrogenic and contractile myofibroblasts [9], [10]. This is accompanied by a series of changes in gene expression patterns that collectively give rise to responses that include cell proliferation and contractility, fibrogenesis, chemotaxis, new and altered ECM deposition, cytokine release and LD loss [9], [10].…”

Section: Discussionmentioning

confidence: 99%

“…However, following liver injury, whether due to chronic alcohol consumption, viral infection, xenobiotic exposure, iron overload or another less common insult, HSCs undergo a process known as activation, which is a transition of quiescent cells into proliferative, fibrogenic and contractile myofibroblasts [9], [10]. This is accompanied by a series of changes in gene expression patterns that collectively give rise to responses that include cell proliferation and contractility, fibrogenesis, chemotaxis, new and altered ECM deposition, cytokine release and LD loss [9], [10]. Free fatty acids released by LD degradation are thought to serve as energy sources for trans-differentiation of HSCs into myofibroblast-like cells to produce fiber including α-SMA and collagen, suggesting that LD degradation closely correlates to HSC activation [9], [10].…”

Section: Discussionmentioning

confidence: 99%

“…Quiescent HSCs release LDs depending on the extracellular retinol status [8]. 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].…”

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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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2017

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MicroRNA‐1254 contributes to the controlling of pro‐fibrogenic environment in LX‐2 cells by modulating SMAD3 and wound repair: new insights in hepatic fibrosis

Gonçalves

Silva

Scarinci

et al. 2019

Cell Biology International

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Hepatic fibrosis and its end‐stage cirrhosis have increased worldwide, and, despite all the efforts, no successful therapy is available. More recently, the heptapeptide angiotensin‐(1‐7) [ang‐(1‐7)] was reported to be able to modulate liver fibrosis and even steatosis; however, the molecular bases of these effects are not clear. In this study, we investigated the overexpression of the microRNA‐1254 in the human hepatic stellate cell line LX‐2, based on the effect of the heptapeptide in such cells, previously, demonstrated by our research group. In addition, this miRNA was chosen based on the identification of putative binding site of this small molecule in the mRNA sequences of different molecular connectors of the AKT/ PI3K pathway, which is modulated by the heptapeptide and connects to the control of several cellular mechanisms, including proliferation, survival, migration, and even liver fibrogenesis. The results revealed an innovative function of the miR‐1254 in controlling SMAD3 and pro‐fibrosing elements as well as the wound healing response in LX‐2, attenuating the scaring repair of the injured tissue. The combined findings provide useful information for future studies on the controlling of hepatic fibrogenesis.

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Crosstalk of LKB1‐regulated and PTEN‐regulated signals in liver morphogenesis and tumor development in mice

Jia

Medina

Liu

et al. 2017

Hepatology Communications

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Liver kinase B 1 (LKB1 or STK11) and PTEN (phosphatase and tensin homologue deleted on chromosome 10) are two tumor suppressors that regulate the mTOR signaling pathway. Deletion studies show that loss of either Lkb1 (Lkb+/−) or Pten (PtenloxP/loxP; Alb-Cre+) leads to liver injury and development of hepatocarcinoma. In this study, we investigated the crosstalk of LKB1 and PTEN loss during tumorigenesis and liver development. We show here that haplo-insufficiency of Lkb1 in the liver leads to advanced tumor development in the Pten null mice (PtenloxP/loxP; LkbloxP/+; Alb-Cre+). Our analysis shows that LKB1 and PTEN interacted with each other in their regulation of fatty acid synthase as well as p21 expression. The combined loss of LKB1 and PTEN (PtenloxP/loxP; LkbloxP/loxP; Alb-Cre+) also led to the inability to form zonal structures in the liver. The lack of metabolic zonal structures is consistent with the inability of the livers to store glycogen as well as elevated plasma bilirubin and alanine aminotransferase (ALT), indicative of liver dysfunction. These structural and functional defects are associated with cytoplasm distribution of a canalicular membrane protein MRP2 (multidrug resistant protein 2) which is responsible for clearing bilirubin. This observed regulation of MRP2 by LKB1 likely contributed to the lack of cellular polarity and the early lethality phenotype associated with homozygous loss of Lkb1 alone or in combination with Pten. Finally, Pten deletion does not rescue the precocious ductal plate formation reported for Lkb1 deleted livers. Conclusion: Our study dissected the functional and molecular crosstalk of PTEN and LKB1 and elucidate key molecular targets for such interaction.

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Activation of hepatic stellate cell in Pten null liver injury model

Cited by 39 publications

References 27 publications

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

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

MicroRNA‐1254 contributes to the controlling of pro‐fibrogenic environment in LX‐2 cells by modulating SMAD3 and wound repair: new insights in hepatic fibrosis

Crosstalk of LKB1‐regulated and PTEN‐regulated signals in liver morphogenesis and tumor development in mice

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