ArticleThe Journal of biological chemistry2013
Protection of a ceramide synthase 2 null mouse from drug-induced liver injury: role of gap junction dysfunction and connexin 32 mislocalization.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 35 citations in OpenAlex.
- Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation.Cell biology and toxicology · 2024Article
- The Role of Longevity Assurance Homolog 2/Ceramide Synthase 2 in Bladder Cancer.International journal of molecular sciences · 2023Review
- Neuronal Ganglioside and Glycosphingolipid (GSL) Metabolism and Disease : Cascades of Secondary Metabolic Errors Can Generate Complex Pathologies (in LSDs).Advances in neurobiology · 2023Article
- Article
- Ceramide/protein phosphatase 2A axis is engaged in gap junction impairment elicited by PCB153 in liver stem-like progenitor cells.Molecular and cellular biochemistry · 2021Article
- Sphingolipid metabolism as a marker of hepatotoxicity in drug-induced liver injury.Prostaglandins & other lipid mediators · 2020Article
- Involvement of gap junctions in propylthiouracil-induced cytotoxicity in BRL-3A cells.Experimental and therapeutic medicine · 2019Article
- A network of chaperones prevents and detects failures in membrane protein lipid bilayer integration.Nature communications · 2019Article
- Role of ceramide synthase 2 in G-CSF signaling and G-CSF-R translocation into detergent-resistant membranes.Scientific reports · 2019Article
- Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate-induced colitis in mice due to increased intestinal permeability.Journal of cellular and molecular medicine · 2017Article
- Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice.Toxicology letters · 2017Article
- Ceramide synthase 2 deficiency aggravates AOM-DSS-induced colitis in mice: role of colon barrier integrity.Cellular and molecular life sciences : CMLS · 2017Article
- Alterations in endo-lysosomal function induce similar hepatic lipid profiles in rodent models of drug-induced phospholipidosis and Sandhoff disease.Journal of lipid research · 2017Article
- Oxidative stress elicited by modifying the ceramide acyl chain length reduces the rate of clathrin-mediated endocytosis.Journal of cell science · 2017Article
- Connexin-based signaling and drug-induced hepatotoxicity.Journal of clinical and translational research · 2017Article
- Critical Role for Very-Long Chain Sphingolipids in Invariant Natural Killer T Cell Development and Homeostasis.Frontiers in immunology · 2017Article
- Sphingolipids and mitochondrial apoptosis.Journal of bioenergetics and biomembranes · 2016Review
- Bortezomib alleviates drug-induced liver injury by regulating CYP2E1 gene transcription.International journal of molecular medicine · 2016Article
- Connexin32: a mediator of acetaminophen-induced liver injury?Toxicology mechanisms and methods · 2016Article
- Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy.Scientific reports · 2015Article
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
Very long chain (C22-C24) ceramides are synthesized by ceramide synthase 2 (CerS2). A CerS2 null mouse displays hepatopathy because of depletion of C22-C24 ceramides, elevation of C16-ceramide, and/or elevation of sphinganine. Unexpectedly, CerS2 null mice were resistant to acetaminophen-induced hepatotoxicity. Although there were a number of biochemical changes in the liver, such as increased levels of glutathione and multiple drug-resistant protein 4, these effects are unlikely to account for the lack of acetaminophen toxicity. A number of other hepatotoxic agents, such as d-galactosamine, CCl4, and thioacetamide, were also ineffective in inducing liver damage. All of these drugs and chemicals require connexin (Cx) 32, a key gap junction protein, to induce hepatotoxicity. Cx32 was mislocalized to an intracellular location in hepatocytes from CerS2 null mice, which resulted in accelerated rates of its lysosomal degradation. This mislocalization resulted from the altered membrane properties of the CerS2 null mice, which was exemplified by the disruption of detergent-resistant membranes. The lack of acetaminophen toxicity and Cx32 mislocalization were reversed upon infection with recombinant adeno-associated virus expressing CerS2. We establish that Gap junction function is compromised upon altering the sphingolipid acyl chain length composition, which is of relevance for understanding the regulation of drug-induced liver injury.
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