Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors

Issa, Razao; Williams, Eleri; Trim, Nathan; Kendall, Timothy J.; Arthur, Michael J. P.; Reichen, J.; Benyon, R. Christopher; Iredale, John P.

doi:10.1136/gut.48.4.548

Cited by 289 publications

(221 citation statements)

References 24 publications

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“…In addition, direct interactions with ECM components leading to activation of the FAK/PI-3K-dependent survival pathway [26], and the secretion of TIMP-1 thereby preventing MMP-dependent matrix degradation [27] may promote the survival of activated HSC. Finally, autocrine stimulation by cytokines like TGF-β or IGF-1 was regarded as a potential protective mechanism [28,29]. In the in vitro model presented here, co-incubation of HSC with CM of steatotic hepatocytes significantly reduced STS-induced apoptotic cell death.…”

Section: Discussionmentioning

confidence: 87%

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

et al. 2009

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Abbreviations: CM (conditioned medium); FFAs (free fatty acids); HSC (hepatic stellate cells); NAFLD (non-alcoholic fatty liver disease); NASH (non-alcoholic steatohepatitis); MMP (matrix-metallo-proteinase); NFκB (nuclear-factor κB); PHH (primary human hepatocytes); TIMP-1/-2 (tissue inhibitor of metallo-proteinase-1/-2) Despite the initial belief that non-alcoholic fatty liver disease is a benign disorder, it is now recognized that fibrosis progression occurs in a significant number of patients. Furthermore, hepatic steatosis has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of other liver diseases. Here, we established an in vitro model to study the effect of hepatic lipid accumulation on hepatic stellate cells (HSCs), the central mediators of liver fibrogenesis. Primary human hepatocytes were incubated with the saturated fatty acid palmitate to induce intracellular lipid accumulation. Subsequently, human HSCs were incubated with conditioned media (CM) from steatotic or control hepatocytes. Lipid accumulation in hepatocytes induced the release of factors that accelerated the activation and proliferation of HSC, and enhanced their resistance to apoptosis, largely mediated via activation of the PI-3-kinase pathway. Furthermore, CM from steatotic hepatocytes induced the expression of the profibrogenic genes TGF-β, tissue inhibitor of metallo-proteinase-1 (TIMP-1), TIMP-2 and matrix-metallo-proteinase-2, as well as nuclear-factor κB-dependent MCP-1 expression in HSC. In summary, our in vitro data indicate a potential mechanism for the pathophysiological link between hepatic steatosis and fibrogenesis in vivo. Herewith, this study provides an attractive in vitro model to study the molecular mechanisms of steatosis-induced fibrogenesis, and to identify and test novel targets for antifibrotic therapies in fatty liver disease.

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Section: Discussionmentioning

confidence: 87%

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

et al. 2009

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“…6G). Furthermore, apoptosis in HSC-T6 cells was induced by serum deprivation plus CHX treatment (32). A significant increase in apoptosis was achieved in HSCs after 4-h incubation with CHX.…”

Section: Mir-21 Pdcd4 and Ap-1 Formed An Autoregulatory Feedback Lomentioning

confidence: 98%

The Autoregulatory Feedback Loop of MicroRNA-21/Programmed Cell Death Protein 4/Activation Protein-1 (MiR-21/PDCD4/AP-1) as a Driving Force for Hepatic Fibrosis Development

Zhang

Zha

et al. 2013

Journal of Biological Chemistry

112

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Background: MicroRNA-21 is important in hepatic fibrosis development, but the mechanism is unclear. Results: MicroRNA-21 is predominantly up-regulated in activated hepatic stellate cells and could form a double negative feedback loop that links fibrogenic machinery. Conclusion:The microRNA-21-mediated loop is a main driving force for hepatic fibrosis progression. Significance: It suggests a mechanism for how microRNA-21 contributes to hepatic fibrosis.Sustained activation of hepatic stellate cells (HSCs) leads to hepatic fibrosis, which is characterized by excessive collagen production, and for which there is no available drug clinically. Despite tremendous progress, the cellular activities underlying HSC activation, especially the driving force in the perpetuation stage, are only partially understood. Recently, microRNA-21 (miR-21) has been found to be prevalently up-regulated during fibrogenesis in different tissues, although its detailed role needs to be further elucidated. In the present study, miR-21 expression was examined in human cirrhotic liver samples and in murine fibrotic livers induced by thioacetamide or carbon tetrachloride. A dramatic miR-21 increase was noted in activated HSCs. We further found that miR-21 maintained itself at constant high levels by using a microRNA-21/programmed cell death protein 4/activation protein-1 (miR-21/PDCD4/AP-1) feedback loop. Disrupting this loop with miR-21 antagomir or AP-1 inhibitors significantly suppressed fibrogenic activities in HSCs and ameliorated liver fibrosis. In contrast, reinforcing this loop with small interfering RNA (siRNA) against PDCD4 promoted fibrogenesis in HSCs. Further analysis indicated that the up-regulated miR-21 promoted the central transforming growth factor-␤ (TGF-␤) signaling pathway underlying HSC activation. In summary, we suggest that the miR-21/PDCD4/AP-1 autoregulatory loop is one of the main driving forces for hepatic fibrosis progression. Targeting this aberrantly activated feedback loop may provide a new therapeutic strategy and facilitate drug discovery against hepatic fibrosis.Hepatic fibrosis is a wound healing process in response to chronic liver injuries that leads to unbalanced extracellular matrix (ECM) 3 deposition and resolution. The persistent activation of wound healing responses causes quantitative and qualitative changes in the ECM components and could finally distort liver parenchyma and vascular architecture, which could impair liver function and potentially lead to liver failure and hepatocellular carcinoma. Following liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into myofibroblast-like cells that are characterized by the expression of smooth muscle ␣-actin (␣-SMA) and enhanced production of ECM (1). Despite the tremendous progress in understanding the mechanisms during fibrogenesis, the driving force underlying the persistent fibrogenic activities is still only partially understood.Extensive studies have suggested the central role of feedback networks in dictating disease progressi...

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“…9 Decreased activity of TIMPs' , apoptosis of HSCs, and even reversal of activated HSCs to a more quiescent state are suggested as key events for fibrosis resolution. 10,11 As activated HSCs are a major source of fibrillar collagens and of TIMPs, clearance of HSCs could facilitate matrix remodeling. Indeed, several studies have demonstrated that clearing HSCs reverses fibrosis.…”

mentioning

confidence: 99%

Osteopontin delays resolution of liver fibrosis

Leung

Wang

Kitamura

et al. 2013

Laboratory Investigation

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To date, considerable progress has been made both in the mechanisms driving liver fibrosis and in the prevention of disease progression. Resolution of liver fibrosis is an emerging field in hepatology; yet, the mediators involved remain elusive. Earlier work from our laboratory demonstrated that the matricellular cytokine osteopontin (OPN) is pro-fibrogenic by promoting hepatic stellate cell (HSC) activation and extracellular matrix (ECM) deposition in vitro and in vivo and specifically by governing fibrillar collagen-I expression, the key pro-fibrogenic protein. Here we hypothesized that OPN could also delay the resolution of liver fibrosis by sustaining collagen-I synthesis or by preventing its degradation. To demonstrate this, wild-type (WT) and OPN-knockout (Opn À / À ) mice were administered thioacetamide (TAA) in the drinking water for 4 months. Half of the mice were killed at 4 months to assess the extent of fibrosis at the peak of injury, and the rest of the mice were killed 2 months after TAA withdrawal to determine the rate of fibrosis resolution. Following TAA cessation, livers from Opn À / À mice showed no centrilobular and parenchymal necrosis along with faster ECM remodeling than WT mice. The latter was quantified by less fibrillar collagen-I immunostaining. Western blot analysis demonstrated a significant decrease in fibrillar collagen-I and in tissue inhibitor of metalloproteinase-1 (TIMP-1) in Opn À / À mice undergoing fibrosis resolution compared with WT mice. In conclusion, these results suggest that OPN delays liver fibrosis resolution due to sustained fibrillar collagen-I deposition; hence, inhibiting OPN could be an effective therapeutic strategy for resolving liver fibrosis.

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Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors

Cited by 289 publications

References 24 publications

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

The Autoregulatory Feedback Loop of MicroRNA-21/Programmed Cell Death Protein 4/Activation Protein-1 (MiR-21/PDCD4/AP-1) as a Driving Force for Hepatic Fibrosis Development

Osteopontin delays resolution of liver fibrosis

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