ArticleEBioMedicine2019
Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 46 citations in OpenAlex.
- Cross-Organ Neuroimmunology of Behavior.Annual review of immunology · 2026Review
- Oleuropein modulates behavioral changes, apoptosis, autophagy, inflammation, oxidative stress-associated PI3K/Akt/mTOR pathways in TAA-Induced hepatic encephalopathy.Metabolic brain disease · 2026Article
- Chemotactic Zn micromotor for treatment of high blood ammonia-associated hepatic encephalopathy.Nature communications · 2025Article
- Lysosomal acidification impairment in astrocyte-mediated neuroinflammation.Journal of neuroinflammation · 2025Review
- β-Catenin/c-Myc Axis Modulates Autophagy Response to Different Ammonia Concentrations.Advanced biology · 2025Article
- Linking Brain and Immune Transcriptomes to Gut-Derived Metabolites in Hepatic Encephalopathy: An Explorative Integrative Multi-Omics Approach.Hepatic medicine : evidence and research · 2025Article
- TGM2-Mediated Autophagy Contributes to the Radio-Resistance of Non-Small Cell Lung Cancer Stem-like Cells.Biomedicines · 2024Article
- Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy.Journal of Zhejiang University. Science. B · 2024Article
- Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice.Journal of neuroinflammation · 2024Article
- Lessons on brain edema in HE: from cellular to animal models and clinical studies.Metabolic brain disease · 2024Review
- Ammonium chloride reduces excitatory synaptic transmission onto CA1 pyramidal neurons of mouse organotypic slice cultures.Frontiers in cellular neuroscience · 2024Article
- Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.International journal of molecular sciences · 2023Review
- Cellular Pathogenesis of Hepatic Encephalopathy: An Update.Biomolecules · 2023Review
- Peroxiredoxin 6 Regulates Glutathione Peroxidase 1-Medited Glutamine Synthase Preservation in the Hippocampus of Chronic Epilepsy Rats.Antioxidants (Basel, Switzerland) · 2023Article
- SDC1-TGM2-FLOT1-BHMT complex determines radiosensitivity of glioblastoma by influencing the fusion of autophagosomes with lysosomes.Theranostics · 2023Article
- Hepatic encephalopathy.Nature reviews. Disease primers · 2022Review
- Metabolomic analysis of vascular cognitive impairment due to hepatocellular carcinoma.Frontiers in neurology · 2022Article
- Genome-Wide Knockout Screen Identifies EGLN3 Involving in Ammonia Neurotoxicity.Frontiers in cell and developmental biology · 2022Article
- The neurogliovascular unit in hepatic encephalopathy.JHEP reports : innovation in hepatology · 2021Review
- Progress on mitochondrial silence information regulator family in epilepsy.Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2021Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
backgroundHepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by various types of liver failure resulting in hyperammonemia-induced dysfunction of astrocytes. It is unclear whether autophagy, an important pro-survival pathway, is altered in the brains of ammonia-intoxicated animals as well as in HE patients.
methodsUsing primary rat astrocytes, a co-culture model of primary mouse astrocytes and neurons, an in vivo rat HE model, and post mortem brain samples of liver cirrhosis patients with HE we analyzed whether and how hyperammonemia modulates autophagy.
findingsWe show that autophagic flux is efficiently inhibited after administration of ammonia in astrocytes. This occurs in a fast, reversible, time-, dose-, and ROS-dependent manner and is mediated by ammonia-induced changes in intralysosomal pH. Autophagic flux is also strongly inhibited in the cerebral cortex of rats after acute ammonium intoxication corroborating our results using an in vivo rat HE model. Transglutaminase 2 (TGM2), a factor promoting autophagy, is upregulated in astrocytes of in vitro- and in vivo-HE models as well as in post mortem brain samples of liver cirrhosis patients with HE, but not in patients without HE. LC3, a commonly used autophagy marker, is significantly increased in the brain of HE patients. Ammonia also modulated autophagy moderately in neuronal cells. We show that taurine, known to ameliorate several parameters caused by hyperammonemia in patients suffering from liver failure, is highly potent in reducing ammonia-induced impairment of autophagic flux. This protective effect of taurine is apparently not linked to inhibition of mTOR signaling but rather to reducing ammonia-induced ROS formation.
interpretationOur data support a model in which autophagy aims to counteract ammonia-induced toxicity, yet, as acidification of lysosomes is impaired, possible protective effects thereof, are hampered. We propose that modulating autophagy in astrocytes and/or neurons, e.g. by taurine, represents a novel strategy to treat liver diseases associated with HE.
fundingSupported by the DFG, CRC974 "Communication and Systems Relevance in Liver Injury and Regeneration", Düsseldorf (Project number 190586431) Projects A05 (DH), B04 (BG), B05 (NK), and B09 (ASR).
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