Role of YAP in Liver Regeneration After Acetaminophen Overdose
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ABSTRACT:
PROVIDER: PRJNA759224 | ENA |
REPOSITORIES: ENA
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Project description:Overdose of acetaminophen (APAP) is the major cause of acute liver failure in the Western world with very limited treatment options. Previous studies from our groups and others have shown that timely activation of liver regeneration is a critical determinant of transplant-free survival of APAP-induced acute liver failure (ALF) patients. We used affy microarrays to explore the mechanisms of transcriptional expression in YAP-KO mice after 300mg/kg APAP overdose.
2021-10-04 | GSE183119 | GEO
Project description:Acetaminophen overdose is the most common cause of acute liver injury (ALI) or acute liver failure in the USA. Its pathogenetic mechanisms are incompletely understood. Additional studies are warranted to identify new genetic risk factors for more mechanistic insights and new therapeutic target discoveries. The objective of this study was to explore the role and mechanisms of nicotinamide phosphoribosyltransferase (NAMPT) in acetaminophen-induced ALI. C57BL/6 Nampt gene wild type (Nampt+/+)-, heterozygous knockout (Nampt+/-)-, and overexpression (NamptOE)-mice were treated with overdose of acetaminophen, followed by histological, biochemical, and transcriptomic evaluation of liver injury. The mechanism of Nampt in acetaminophen -induced hepatocytic toxicity was also explored in cultured primary hepatocytes. Three lines of evidence have convergently demonstrated that acetaminophen overdose triggers the most severe oxidative stress and necrosis, and the highest expression of key necrosis driving genes in Nampt+/- mice, while the effects in NamptOE mice were least severe relative to Nampt+/+ mice. These findings support that NAMPT protects against acetaminophen induced ALI.
2018-04-03 | GSE110787 | GEO
Project description:To study the global changes of liver transcriptome after acetaminophen overdose.
2013-05-03 | GSE42181 | GEO
Project description:To study the global changes of liver transcriptome after acetaminophen overdose.
2013-05-03 | GSE42178 | GEO
Project description:To study the global changes of liver transcriptome after acetaminophen overdose. To study the global changes of transcriptome in the liver after acetaminophen overdose. Eight week old female C57BL/6 mice were fasted for 24 hours prior to a single intraperitoneal injection of 350mg/kg of acetaminophen in phosphate buffer saline (PBS) (treatment group) or PBS (control group). The mice were euthanized at different time points post exposure; plasma and tissue samples were collected for pathological examination and biochemical analyses.
2013-05-03 | E-GEOD-42181 | biostudies-arrayexpress
Project description:To study the global changes of liver transcriptome after acetaminophen overdose. To study the global changes of transcriptome in the liver after acetaminophen overdose. Eight week old female C57BL/6 mice were fasted for 24 hours prior to a single intraperitoneal injection of 350mg/kg of acetaminophen in phosphate buffer saline (PBS) (treatment group) or PBS (control group). The mice were euthanized at different time points post exposure; plasma and tissue samples were collected for pathological examination and biochemical analyses.
2013-05-03 | E-GEOD-42178 | biostudies-arrayexpress
Project description:Cardiomyocyte (CM) loss after injury results in adverse remodelling and fibrosis, which inevitably lead to heart failure. Neuregulin-ErbB2 and Hippo-Yap signaling pathways are key mediators of CM proliferation and regeneration although the crosstalk between these pathways is unclear. Here, we demonstrate in mice that temporal over-expression (OE) of activated ErbB2 in CMs promotes cardiac regeneration in a heart failure model. Cellularly, OE CMs present an EMT-like regenerative response involving cytoskeletal reprograming, migration, ECM turnover, and displacement. Molecularly, we identified Yap as a critical mediator of ErbB2 signaling. In OE CMs, Yap interacts with nuclear envelope and cytoskeletal components, reflective of the altered mechanic state elicited by ErbB2. Hippo-independent activating phosphorylation on Yap at S352 and S274 were enriched in OE CMs, peaking during metaphase. Viral overexpression of Yap phospho-mutants dampened the proliferative competence of OE CMs. Taken together, we demonstrate a potent ErbB2-mediated Yap mechanosensory signaling involving EMT-like characteristics, resulting in heart regeneration.
2020-08-21 | PXD020731 | Pride
Project description:There is a paucity of data on how protease-activated receptors (PARs) regulate transcriptional reprogramming. We sought to determine how the expression of two members of the PAR family (PAR1 and PAR4) on hepatic endothelial cells (ECs) influence transcription in the liver after acetaminophen (APAP) overdose. We combined EC-specific translating ribosome affinity purification with next-generation sequencing (EC-TRAPseq) in endothelial-specific Par1 and Par4 knockout mice. This allowed us to gain an in vivo snapshot of how EC gene expression profiles change with APAP overdose and how the loss of endothelial PARs impacts transcriptional reprogramming in hepatic ECs. This approach also provided a high degree of sensitivity for detecting low-expressing transcripts. We found distinct transcriptional changes in APAP-overdosed ECs between endothelial Par1 and Par4 knockout mice.
2024-06-10 | GSE266395 | GEO
Project description:p53 is the major cellular gatekeeper involved in proliferation, cell death, migration, and homeostasis. The role of p53 in pathogenesis of drug-induced liver injury is unknown. We investigated the role of p53 in liver injury and regeneration after acetaminophen (APAP) overdose, the most common cause of acute liver failure in the Western world. Eight-week-old male wild-type (WT) and p53 knockout (p53KO) mice were treated with 300 mg/kg APAP, and the dynamics of liver injury and regeneration were studied over a time course of 0 to 96 hours. Deletion of p53 resulted in a threefold higher liver injury than in WT mice. Interestingly, despite higher liver injury, p53KO mice recovered similarly as the WT mice because of faster liver regeneration. Deletion of p53 did not affect APAP bioactivation and initiation of injury. Microarray analysis revealed that p53KO mice had disrupted metabolic homeostasis and induced inflammatory and proliferative signaling. p53KO mice showed prolonged steatosis correlating with prolonged liver injury. Initiation of liver regeneration in p53KO mice was delayed, but once initiated, cell cycle was significantly faster than WT mice because of sustained AKT, extracellular signal-regulated kinase, and mammalian target of rapamycin signaling. These studies show that p53 plays a pleotropic role after APAP overdose, where it prevents progression of liver injury by maintaining metabolic homeostasis and also regulates initiation of liver regeneration through proliferative signaling.
| S-EPMC5971235 | biostudies-other
Project description:The p21+ Perinecrotic Hepatocytes Produce the Chemokine Cxcl14 After a Severe Acetaminophen Overdose Promoting Hepatocyte Injury and Delaying Regeneration
| PRJNA1076645 | ENA