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Transcriptional analysis of in vivo responses to acetaminophen induced hepatic injury in the murine liver

ABSTRACT: Transcriptional analysis of in vivo responses to acetaminophen induced hepatic injury in the murine liver

PROVIDER: PRJNA438296 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6833760_1.fastq.gz	Fastqsanger.gz
	SRR6833760_2.fastq.gz	Fastqsanger.gz
	SRR6833770_1.fastq.gz	Fastqsanger.gz
	SRR6833770_2.fastq.gz	Fastqsanger.gz
	SRR6833761_1.fastq.gz	Fastqsanger.gz

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Transcriptional analysis of in vivo responses to acetaminophen induced hepatic injury in the murine liver

Project description:Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence underlies this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury model a transcriptional signature associated with the induction of paracrine senescence is observed within twenty four hours, and is followed by one of impaired proliferation. In genetic models of hepatocyte injury and senescence we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended upon macrophage derived TGFβ1 ligand. In acetaminophen poisoning inhibition of TGFβ receptor 1 (TGFβR1) improved survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered after the current therapeutic window. This mechanism, in which injury induced senescence impairs regeneration, is an attractive therapeutic target for acute liver failure.

2019-03-20 | GSE111828 | GEO

Transcriptional analysis of in vivo responses to acetaminophen induced hepatic injury in the murine liver

Project description:Transcriptional analysis of in vivo responses to acetaminophen induced hepatic injury in the murine liver

| PRJNA438296 | ENA

Hepatic responses of mice and rats to equivalent acetaminophen (APAP) insult – SWATH proteomics

Project description:The well-known difference in sensitivity of mice and rats to acetaminophen (APAP) liver injury has been related to differences in the fraction that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Physiologically-based pharmacokinetic modelling was used to identify doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI, to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult.

2023-08-31 | PXD034438 | Pride

Hepatic responses of mice and rats to equivalent acetaminophen (APAP) insult [rat]

2023-06-20 | GSE205202 | GEO

Hepatic responses of mice and rats to equivalent acetaminophen (APAP) insult [mouse]

2023-06-20 | GSE205201 | GEO

Scavenger receptor A ameliorates acetaminophen induced hepatic inflammation

Project description:Acetaminophen-induced liver injury (AILI) occurs frequently and can be life threatening. Although AILI is mainly caused by the direct drug cytotoxicity, increasing evidence suggests that the interplay between hepatocytes and immune cells can define this pathogenic process. To further understand the immunoregulatory role of SRA in AILI, we performed RNA-sequencing analysis using hepatic nonparenchymal cells (NPCs) derived from acetaminophen treated WT or SRA-/- mice to demonstrate hepatocyte-extrinsic mechanisms governed by the immune receptor SRA that maintains liver homeostasis upon drug insult.

2023-12-23 | GSE221747 | GEO

Protein S-nitrosylation Restricts Xenobiotic Receptor PXR Hyperactivity and Ameliorates Acetaminophen-induced Liver Injury in Mice

Project description:Drug-induced liver injury (DILI), especially acetaminophen overdose, is the leading cause of acute liver failure. Pregnane X receptor (PXR) is a nuclear receptor and the master regulator of drug metabolism. Aberrant activation of PXR plays a pathogenic role in the acetaminophen hepatotoxicity. Here, we aimed to examine the PXR S-nitrosylation (SNO) in response to acetaminophen. We found that PXR was S-nitrosylated in hepatocytes and the mouse livers after exposure to acetaminophen or S-nitrosoglutathione (GSNO). Mass-spectrometry and site-directed mutagenesis identified the cysteine 307 as the primary residue for SNO-modification. In hepatocytes, SNO suppressed both agonist (rifampicin and SR12813)-induced and constitutively active PXR (VP-PXR) activations. Furthermore, in acetaminophen overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In PXR-deficient (PXR-/-) mice, replenishing the livers with the SNO-deficient PXR significantly aggravated hepatic necrosis and apoptosis, increased HMGB1 release, and exacerbated liver injury and inflammation. Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of PXR S-nitrosylation. In conclusion, PXR is post-translationally modified by S-nitrosylation in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a new target for therapeutical intervention.

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Novel Protective Role of Nicotinamide Phosphoribosyltransferase in Acetaminophen-induced Acute Liver Injury in Mice

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

Hepatic responses of mice and rats to equivalent acetaminophen (APAP) insult

Project description:Hepatic responses of mice and rats to equivalent acetaminophen (APAP) insult

| PRJNA844087 | ENA

Scavenger receptor A ameliorates acetaminophen induced hepatic inflammation

Project description:Scavenger receptor A ameliorates acetaminophen induced hepatic inflammation

| PRJNA915955 | ENA