Inhibition of TWEAK/Tnfrsf12a axis protects against acute liver failure by suppressing RIPK1-dependent apoptosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE206595 | GEO | 2022/07/18
REPOSITORIES: GEO
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Project description:Inhibition of TWEAK/Tnfrsf12a axis protects against acute liver failure by suppressing RIPK1-dependent apoptosis
| PRJNA851438 | ENA
Project description:Acute liver failure (ALF) is a severe clinical syndrome characterized by massive death of hepatocytes in a short time, resulting in coagulopathy and hepatic encephalopathy, with a high mortality in patients without pre-existing liver disease. Effective treatment of ALF is currently limited to liver transplantation, highlighting the need for new target therapies. Here, we found that expression of hepatic tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor tumor necrosis factor receptor superfamily member 12A (Tnfrsf12a) were significantly increased during ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Inhibition of TWEAK/Tnfrsf12a axis markedly attenuated TAA or APAP-induced ALF. Moreover, our results demonstrated that TWEAK/Tnfrsf12a axis induced receptor-interacting protein kinase 1 (RIPK1)-dependent apoptosis of hepatocytes, instead of necroptosis or pyroptosis. Notably, hepatic TNFRSF12A and TWEAK levels were also significantly increased in liver biopsies from ALF patients. In summary, our results demonstrate that during ALF, TWEAK/Tnfrsf12a axis activates RIPK1 in hepatocytes, leading to RIPK1-dependent apoptosis and subsequent liver injury. Therefore, inhibition of either TWEAK/Tnfrsf12a axis or RIPK1-dependent apoptosis attenuates liver injury, providing a new potential therapeutic target for the treatment of ALF.
| S-EPMC9296540 | biostudies-literature
Project description:Acetaminophen (APAP) is one of the most widely consumed and prescribed drugs. APAP overdose is one of the leading causes of intrinsic drug-induced liver injury (DILI), acute liver failure (ALF), and liver transplantation in the Western world. Mg2+, essential for health, plays a role in virtually every process within the human cell. The cellular transporter family cyclin M, also known as CNNM, plays a key role in Mg2+ transport across the cell membranes in different organs. Here, we identified that the expression of CNNM4 is elevated in the liver of patients with APAP-induced liver injury (AILI), with a concomitant disturbance in serum Mg2+ levels. We demonstrated that, in the liver, APAP interferes with the Mg2+ mitochondrial reservoir via CNNM4, which affects ATP production and ROS generation, further boosting endoplasmic reticulum (ER) stress of the hepatocytes. Importantly, the CNNM4 mutant T495I showed no effect. Finally, a shift in localization of CNNM4 from membrane to ER was shown under APAP toxicity. Therapeutic targeting of Cnnm4 in the liver with nanoparticles and GalNAc-formulated siRNA provides efficient protection from AILI by restoring hepatocyte Mg2+ homeostasis and by inducing hepatocyte restoration. Our results suggest that inhibition of Cnnm4 may represent an alternative route for the treatment of DILI..
2023-03-11 | PXD036682 | Pride
Project description:Acute liver failure is a serious clinical manifestation resulting from sudden liver injury, which can be triggered by various factors. One of the most frequent causes of acute liver failure is excessive ingestion of acetaminophen (APAP), which is known to damage hepatocytes directly by reducing glutathione levels in cells, ultimately leading to hepatocyte death.PGE2 can play a dual role in inflammation, either promoting or inhibiting the inflammatory response, depending on the cell type, local concentration, receptor type, and tissue microenvironment. Early studies have shown that PGE2 significantly alleviated acute liver failure induced by galactosamine/lipopolysaccharide, APAP, and carbon tetrachloride. However, the precise mechanism by which PGE2 alleviates APAP-induced acute liver failure remains unclear. The aim of this study is to investigate the mechanisms underlying the protective effects of PGE2 against APAP-induced hepatocyte injury.
2023-09-01 | GSE241511 | GEO
Project description:Acute liver failure is a serious clinical manifestation resulting from sudden liver injury, which can be triggered by various factors. One of the most frequent causes of acute liver failure is excessive ingestion of acetaminophen (APAP), which is known to damage hepatocytes directly by reducing glutathione levels in cells, ultimately leading to hepatocyte death.PGE2 can play a dual role in inflammation, either promoting or inhibiting the inflammatory response, depending on the cell type, local concentration, receptor type, and tissue microenvironment. Early studies have shown that PGE2 significantly alleviated acute liver failure induced by galactosamine/lipopolysaccharide, APAP, and carbon tetrachloride. However, the precise mechanism by which PGE2 alleviates APAP-induced acute liver failure remains unclear. The aim of this study is to investigate the mechanisms underlying the protective effects of PGE2 against APAP-induced hepatocyte injury.
2023-09-01 | GSE241510 | GEO
Project description:Acute liver failure is a serious clinical manifestation resulting from sudden liver injury, which can be triggered by various factors. One of the most frequent causes of acute liver failure is excessive ingestion of acetaminophen (APAP), which is known to damage hepatocytes directly by reducing glutathione levels in cells, ultimately leading to hepatocyte death.PGE2 can play a dual role in inflammation, either promoting or inhibiting the inflammatory response, depending on the cell type, local concentration, receptor type, and tissue microenvironment. Early studies have shown that PGE2 significantly alleviated acute liver failure induced by galactosamine/lipopolysaccharide, APAP, and carbon tetrachloride. However, the precise mechanism by which PGE2 alleviates APAP-induced acute liver failure remains unclear. The aim of this study is to investigate the mechanisms underlying the protective effects of PGE2 against APAP-induced hepatocyte injury.
2023-09-01 | GSE241509 | GEO
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 (APAP) is the most widely used analgesic in the United States. Its acute overdose causes liver damage by inducing localized centrilobular cell death. Because of widespread use, APAP toxicity has become the most frequent cause of acute liver failure. Many factors have been associated with the susceptibility of APAP-induced liver injuries, however, few of them have been confirmed and used in the clinical setting. We tried to identify the subset of factors that could affect susceptibility to APAP-induced liver injury by an integrative genetic, transcriptional and 2-D-NMR-based metabolomic analysis across a panel of inbred mouse strains.
2009-08-14 | GSE17649 | GEO
Project description:Better biomarkers to predict death early in acute liver failure (ALF) are needed. To that end, we obtained early (study day 1) and later (day 3) serum samples from transplant-free survivors (n=28) and non-survivors (n=30) of acetaminophen (APAP)-induced ALF from the NIH-sponsored Acute Liver Failure Study Group, and from control volunteers (n=10). To identify proteins that increase early in serum during ALF, we selected individuals from this cohort for whom ALT was lower on day 1 than day 3, indicating a time point before the peak of injury (n=10/group). We then performed untargeted proteomics on their day 1 samples. Out of 1,682 quantifiable proteins, 79 were elevated ≥4-fold in ALF patients vs. controls and 23 of those were further elevated ≥4-fold in non-survivors vs. survivors, indicating potential to predict death. Interestingly, the biomarker with best performance was LDH. To confirm the prognostic potential of LDH, we measured activity in all day 1 and 3 samples from all 58 ALF patients. LDH was elevated in the non-survivors vs. survivors on both days. In addition, receiver operating characteristic (ROC) curve analyses revealed that LDH alone performed similarly to the model for end-stage liver disease (MELD), while a combination of MELD and LDH outperformed either alone. Finally, Upstream Analysis of our proteomics data indicated activation of LKB1-AMPK signaling in liver regeneration after APAP overdose and we confirmed that in mice. Overall, we conclude LDH can predict death in APAP-induced ALF and that LKB1-AMPK signaling may be a promising therapeutic target to improve survival.
2022-08-12 | PXD029576 | Pride
Project description:Acetaminophen (APAP) is the most widely used analgesic in the United States. Its acute overdose causes liver damage by inducing localized centrilobular cell death. Because of widespread use, APAP toxicity has become the most frequent cause of acute liver failure. Many factors have been associated with the susceptibility of APAP-induced liver injuries, however, few of them have been confirmed and used in the clinical setting. We tried to identify the subset of factors that could affect susceptibility to APAP-induced liver injury by an integrative genetic, transcriptional and 2-D-NMR-based metabolomic analysis across a panel of inbred mouse strains. Experiment Overall Design: After a single administration of high dose (300 mg/kg i.p.) APAP, liver and blood samples were extracted from 3 sensitive (C57B6, DBA/2, and SmJ) and 1 resistant (SJL) mice strains at 0, 3 and 6 hour after APAP exposure. Endogenous metabolites from liver samples were analyzed by 1H-13C 2-dimensional-NMR and gene expression changes occurring within these liver samples were simultaneously analyzed using Affymetrix microarrays. The transcriptional and metabolomic data was jointly analyzed, and functional information within the Gene Ontology database was used to identify the subset of genes that could affect susceptibility to APAP-induced liver injury in the early phase response.
2009-08-23 | E-GEOD-17649 | biostudies-arrayexpress