A murder mystery in the liver: who done it and how?

Dara, Lily; Liu, Zhang Xu; Kaplowitz, Neil

doi:10.1172/jci90830

Cited by 16 publications

(19 citation statements)

References 22 publications

(20 reference statements)

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“…20 Although these results seem confirmatory, more rigorous studies using littermate controls and inducible liver cell-specific knockout are needed for conclusive results. 22 Furthermore, we could find no change in RIPK3 expression in the short time course APAP toxicity (up to 24 h) in vitro or in vivo .…”

Section: Acute Liver Injury Models In Which Necroptosis Has Been Studiedmentioning

confidence: 71%

“…21 Of course, theoretically in some unique circumstances it is possible that MLKL can be activated in a RIPK3-independent fashion and this has been suggested to occur in immune-mediated liver disease, see ConA section for more details. 20,22 …”

Section: Do Hepatocytes Undergo Necroptosis In Models Of Liver Injury?mentioning

confidence: 99%

“…It is unclear in these studies how MLKL is activated in the absence of RIPK3, but an unidentified kinase downstream of RIPK1 is suggested to contribute to this non-canonical necroptosis pathway which seems to be MLKL-dependent. 20,22 Investigation of conditional and liver-specific knockout models is still warranted.…”

Section: Acute Liver Injury Models In Which Necroptosis Has Been Studiedmentioning

confidence: 99%

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Questions and controversies: the role of necroptosis in liver disease

Dara

Liu

Kaplowitz

2016

Cell Death Discovery

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Acute and chronic liver injury results in hepatocyte death and turnover. If injury becomes chronic, the continuous cell death and turnover leads to chronic inflammation, fibrosis and ultimately cirrhosis and hepatocellular carcinoma. Controlling liver cell death both in acute injury, to rescue the liver from acute liver failure, and in chronic injury, to curb secondary inflammation and fibrosis, is of paramount importance as a therapeutic strategy. Both apoptosis and necrosis occur in the liver, but the occurrence of necroptosis in the liver and its contribution to liver disease is controversial. Necroptosis is a form of regulated necrosis which occurs in certain cell types when caspases (+/−cIAPs) are inhibited through the RIPK1-RIPK3 activation of MLKL. The occurrence of necroptosis in the liver has recently been examined in multiple liver injury models with conflicting results. The aim of this review is to summarize the published data with an emphasis on the controversies and remaining questions in the field.

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Section: Acute Liver Injury Models In Which Necroptosis Has Been Studiedmentioning

confidence: 71%

Section: Do Hepatocytes Undergo Necroptosis In Models Of Liver Injury?mentioning

confidence: 99%

Section: Acute Liver Injury Models In Which Necroptosis Has Been Studiedmentioning

confidence: 99%

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Questions and controversies: the role of necroptosis in liver disease

Dara

Liu

Kaplowitz

2016

Cell Death Discovery

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“…RIPK1 and MLKL are clearly expressed in the liver; however, RIPK3 expression under basal conditions has been controversial. 7,13,14,[78][79][80] RIPK3 induction has been suggested in some models and human diseases. [81][82][83][84][85] While RIPK3 is difficult to detect in freshly isolated hepatocyte, it is robustly expressed in the nonparenchymal cell (NPC) fraction, making it possible that necroptosis occurs in certain cell types in the liver.…”

Section: Ripks In the Livermentioning

confidence: 99%

“…78 A RIPK3-independent model for necroptosis in hepatocytes has been suggested, and since MLKL is clearly present in the liver, it is hypothesized that other MLKL activators exist. 79,80 RIPKs in APAP Toxicity and Hepatocyte Death RIPK1 was the first family member studied in liver disease due to the availability of nec-1, the RIPK1 kinase inhibitor which was shown to protect against necrotic cell death in multiple organ systems. 41,42 Using nec-1 multiple investigator demonstrated a survival benefit against acetaminophen (APAP)-induced liver injury in mice and in hepatocytes in vitro.…”

Section: Ripks In the Livermentioning

confidence: 99%

The Receptor Interacting Protein Kinases in the Liver

Dara

2018

Semin Liver Dis

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The Receptor Interacting serine/threonine Kinase1 and 3 (RIPK1, RIPK3) are regulators of cell death and survival. RIPK1 kinase activity is required for necroptosis and apoptosis, while its scaffolding function is necessary for survival. Although both proteins can mediate apoptosis, RIPK1 and RIPK3 are most well-known for their role in the execution of necroptosis via the pseudokinase mixed lineage domain like (MLKL). Necroptosis is a caspase-independent regulated cell death program which was first described in cultured cells with unknown physiologic relevance in the liver. Many recent reports have suggested that RIPK1 and/or RIPK3 participate in liver disease pathogenesis and cell death. Notably, both proteins have been shown to mediate inflammation independent of cell death. Whether necroptosis occurs in hepatocytes, and how it is executed in the presence of an intact caspase machinery is controversial. In spite of this controversy, it is evident that RIPK1 and RIPK3 participate in many experimental liver disease models. Therefore, in addition to cell death signaling, their necroptosis independent role warrants further examination.

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Hippo Pathway Activation in Aged Mesenchymal Stem Cells Contributes to the Dysregulation of Hepatic Inflammation in Aged Mice

et al. 2023

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Aging is always accompanied by chronic diseases which probably attribute to long‐term chronic inflammation in the aging body. Whereas, the mechanism of chronic inflammation in aging body is still obscure. Mesenchymal stem cells (MSCs) are capable of local chemotaxis to sites of inflammation and play a powerful role in immune regulation. Whether degeneration of MSCs in the aging body is associated with unbalanced inflammation is still not clear. In this study, immunosuppressive properties of aged MSCs are found to be repressed. The impaired immunosuppressive function of aged MSCs is associated with lower expression of the Hippo effector Yes‐associated protein 1 (YAP1) and its target gene signal transducer and activator of transcription 1 (STAT1). YAP1 regulates the transcription of STAT1 through binding with its promoter. In conclusion, a novel YAP1/STAT1 axis maintaining immunosuppressive function of MSCs is revealed and impairment of this signal pathway in aged MSCs probably resulted in higher inflammation in aged mice liver.

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A murder mystery in the liver: who done it and how?

Cited by 16 publications

References 22 publications

Questions and controversies: the role of necroptosis in liver disease

Questions and controversies: the role of necroptosis in liver disease

The Receptor Interacting Protein Kinases in the Liver

Hippo Pathway Activation in Aged Mesenchymal Stem Cells Contributes to the Dysregulation of Hepatic Inflammation in Aged Mice

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