Hepatocyte-specific MET deletion exacerbates acetaminophen-induced hepatotoxicity in mice
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ABSTRACT:
PROVIDER: PRJNA1306461 | ENA |
REPOSITORIES: ENA
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Project description:Despite the well-known role of MET in liver regeneration following partial-hepatectomy (PHx), its role in the clinically-relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from PHx because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET-KO mice were given a toxic-dose of APAP and assessed for hepatotoxicity/regeneration parameters. MET deletion strikingly exacerbated initial hepatotoxicity and impaired subsequent proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced JNK-activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative-damage, releasing cell-death inducer AIF into cytosol. Excess JNK-activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET-signaling. Pharmacological activation of AKT reduced JNK-activation and hepatotoxicity in MET-KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling, but also activation of cell death/senescence pathways along with impaired unfolded-protein-response in MET-KO mice. Analysis of published single-nucleus RNA-sequencing data showed proliferation in livers from APAP-induced ALF patients was associated with strong activation of HGF/MET signaling in hepatocytes, with spatial-transcriptomics showing striking induction of HGF surrounding the necrotic-zones. Interestingly, 35% of the genes altered in human-ALF were regulated by MET in the mouse AILI-model. In conclusion, our study demonstrates that MET is crucial for restraining hepatotoxicity following APAP overdose via inhibiting mitochondrial cell-death signaling pathway.
2025-09-10 | GSE305543 | GEO
Project description:Dendritic cell iron overload exacerbates acetaminophen hepatotoxicity
| PRJNA1198320 | ENA
Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms.
2013-08-30 | GSE34442 | GEO
Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms, possibly through transcriptional regulation of cytochrome p450-oxidoreductase (Por).
2013-08-30 | GSE34443 | GEO
Project description:Liver immune homeostasis relies on the coordinated actions of various immune cells including dendritic cells (DCs), which exert regulatory roles in both innate and adaptive immunity. Various pieces of evidence demonstrate that the properties of immune cells are highly influenced by iron metabolism. However, the roles of iron metabolism on DC function remain poorly understood. Here, we show that mice with iron overload in DCs displayed worsening of liver injury and mortality in acetaminophen (APAP) -induced acute hepatitis. Enhanced neutrophil infiltration was observed in these mice during the progression of liver injury. DCs with iron overload showed increased expression of the neutrophil-attracting cytokine IL-6, thereby accelerating liver injury. Mechanistic studies revealed that iron enhanced the recruitment of NF-κB to the IL-6 promoter upon TLR4 activation. Our findings provide an insight into the regulatory mechanisms by which iron metabolism influences DC function. This study also highlights the critical role of the DC-IL-6-neutrophil axis in acute liver injury.
2025-05-22 | GSE284273 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one third of the global population. Understanding metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific
ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated
acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.
2023-12-12 | MSV000093653 | MassIVE
Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms, possibly through transcriptional regulation of cytochrome p450-oxidoreductase (Por). 10-20 week old Mop3fxfx mice positive or negative for Cre-recombinase driven by the albumin promoter, housed in 12 hour light:12 dark, ad lib feeding and drinking conditions were sacrificed every four hours over two separte days beginning at ZT0. A two color, reference design experiment in which kidney RNA from at least 3 mice per timepoint were pooled and labeled with Cy3 and hybridized according to Agilent protocols against a reference pool of RNA madeup from respective tissue taken from 10 week Mop3fxfx and Mop3fxfxCreAlb mice which was labeled with Cy5.
2013-08-30 | E-GEOD-34443 | biostudies-arrayexpress
Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms. 10-20 week old Mop3fxfx mice positive or negative for Cre-recombinase driven by the albumin promoter, housed in 12 hour light:12 dark, ad lib feeding and drinking conditions were sacrificed every four hours over two separte days beginning at ZT0. A two color, reference design experiment in which liver RNA from at least 3 mice per timepoint were pooled and labeled with Cy3 and hybridized according to Agilent protocols against a reference pool of RNA madeup from respective tissue taken from 10 week Mop3fxfx and Mop3fxfxCreAlb mice which was labeled with Cy5.
2013-08-30 | E-GEOD-34442 | biostudies-arrayexpress
Project description:Differential gene expression in mice liver after carbon tetrachloride and acetaminophen administration. Livers from control mice were compared with drug treated mice livers at different time points. Keywords: Time-course
2007-02-27 | GSE4874 | GEO
Project description:Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure in the United States and is primarily mediated by toxic metabolites that accumulate in the liver upon depletion of glutathione stores. However, cells of the innate immune system, including natural killer (NK) cells, neutrophils, and Kupffer cells, have also been implicated in the centrilobular liver necrosis associated with APAP. We have recently shown that dendritic cells (DCs) regulate intrahepatic inflammation in chronic liver disease and, therefore, postulated that DC may also modulate the hepatotoxic effects of APAP. We found that DC immune-phenotype was markedly altered after APAP challenge. In particular, liver DC expressed higher MHC II, costimulatory molecules, and Toll-like receptors, and produced higher interleukin (IL)-6, macrophage chemoattractant protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-?). Conversely, spleen DC were unaltered. However, APAP-induced centrilobular necrosis, and its associated mortality, was markedly exacerbated upon DC depletion. Conversely, endogenous DC expansion using FMS-like tyrosine kinase 3 ligand (Flt3L) protected mice from APAP injury. Our mechanistic studies showed that APAP liver DC had the particular capacity to prevent NK cell activation and induced neutrophil apoptosis. Nevertheless, the exacerbated hepatic injury in DC-depleted mice challenged with APAP was independent of NK cells and neutrophils or numerous immune modulatory cytokines and chemokines.Taken together, these data indicate that liver DC protect against APAP toxicity, whereas their depletion is associated with exacerbated hepatotoxicity.
| S-EPMC3166555 | biostudies-literature