ArticleThe Journal of clinical investigation2003
Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice.
Article in The Journal of clinical investigation, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 224 citations in OpenAlex.
- Contradictory Effects on Hepatocytes in ASMD.International journal of molecular sciences · 2026Review
- Short-Term Acid Sphingomyelinase Deficiency Exerts Proinflammatory and Antiapoptotic Effects during LPS-induced Lung Injury in Mice.American journal of respiratory cell and molecular biology · 2025Article
- Alleviating Effects of Vitamins E and D on Tamoxifen-Induced Hepatotoxicity in Female Wistar Rats.Chonnam medical journal · 2025Article
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- Environmental Temperature Variation Affects Brain Lipid Composition in Adult Zebrafish (International journal of molecular sciences · 2024Article
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- Ceramide on the road to insulin resistance and immunometabolic disorders in transition dairy cows: driver or passenger?Frontiers in immunology · 2023Review
- You aren't IMMUNE to the ceramides that accumulate in cardiometabolic disease.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2022Article
- Review
- Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids.Frontiers in immunology · 2022Review
- Review
- Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency.American journal of respiratory cell and molecular biology · 2021Article
- Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Roles of Ceramides in Non-Alcoholic Fatty Liver Disease.Journal of clinical medicine · 2021Review
- Lithium Hydroxide Hydrolysis Combined with MALDI TOF Mass Spectrometry for Rapid Sphingolipid Detection.Journal of the American Society for Mass Spectrometry · 2021Article
- Sphingolipid metabolism as a marker of hepatotoxicity in drug-induced liver injury.Prostaglandins & other lipid mediators · 2020Article
- Metabolomic Signature as a Predictor of Liver Disease Events in Patients With HIV/HCV Coinfection.The Journal of infectious diseases · 2020Article
- Sphingomyelinases and Liver Diseases.Biomolecules · 2020Review
- Dysregulated metabolic pathways in age-related macular degeneration.Scientific reports · 2020Article
- Hepatic pathology and altered gene transcription in a murine model of acid ceramidase deficiency.Laboratory investigation; a journal of technical methods and pathology · 2019Article
35 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
This study addressed the contribution of acidic sphingomyelinase (ASMase) in TNF-alpha-mediated hepatocellular apoptosis. Cultured hepatocytes depleted of mitochondrial glutathione (mGSH) became sensitive to TNF-alpha, undergoing a time-dependent apoptotic cell death preceded by mitochondrial membrane depolarization, cytochrome c release, and caspase activation. Cyclosporin A treatment rescued mGSH-depleted hepatocytes from TNF-alpha-induced cell death. In contrast, mGSH-depleted hepatocytes deficient in ASMase were resistant to TNF-alpha-mediated cell death but sensitive to exogenous ASMase. Furthermore, although in vivo administration of TNF-alpha or LPS to galactosamine-pretreated ASMase(+/+) mice caused liver damage, ASMase(-/-) mice exhibited minimal hepatocellular injury. To analyze the requirement of ASMase, we assessed the effect of glucosylceramide synthetase inhibition on TNF-alpha-mediated apoptosis. This approach, which blunted glycosphingolipid generation by TNF-alpha, protected mGSH-depleted ASMase(+/+) hepatocytes from TNF-alpha despite enhancement of TNF-alpha-stimulated ceramide formation. To further test the involvement of glycosphingolipids, we focused on ganglioside GD3 (GD3) because of its emerging role in apoptosis through interaction with mitochondria. Analysis of the cellular redistribution of GD3 by laser scanning confocal microscopy revealed the targeting of GD3 to mitochondria in ASMase(+/+) but not in ASMase(-/-) hepatocytes. However, treatment of ASMase(-/-) hepatocytes with exogenous ASMase induced the colocalization of GD3 and mitochondria. Thus, ASMase contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the mitochondrial targeting of glycosphingolipids.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.