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Roles for C16-ceramide and Sphingosine 1-Phosphate in Regulating Hepatocyte Apoptosis in Response to Tumor Necrosis Factor-α
Open accessAbstract
Tumor necrosis factor (TNF)-alpha signals cell death and simultaneously induces the generation of ceramide, which is metabolized to sphingosine and sphingosine 1-phosphate (S1P) by ceramidase (CDase) and sphingosine kinase. Because the dynamic balance between the intracellular levels of ceramide and S1P (the "ceramide/S1P rheostat") may determine cell survival, we investigated these sphingolipid signaling pathways in TNF-alpha-induced apoptosis of primary hepatocytes. Endogenous C16-ceramide was elevated during TNF-alpha-induced apoptosis in both rat and mouse primary hepatocytes. The putative acid sphingomyelinase (ASMase) inhibitor imipramine inhibited TNF-alpha-induced apoptosis and C16-ceramide increase as did the knock out of ASMase. Overexpression of neutral CDase (NCDase) inhibited the TNF-alpha-induced increase of C16-ceramide and apoptosis in rat primary hepatocytes. Moreover, NCDase inhibited liver injury and hepatocyte apoptosis in mice treated with D-galactosamine plus TNF-alpha. This protective effect was abrogated by the sphingosine kinase inhibitor N,N-demethylsphingosine, suggesting that the survival effect of NCDase is due to not only C16-ceramide reduction but also S1P formation. Administration of S1P or overexpression of NCDase activated the pro-survival kinase AKT, and overexpression of dominant negative AKT blocked the survival effect of NCDase. In conclusion, activation of ASMase and generation of C16-ceramide contributed to TNF-alpha-induced hepatocyte apoptosis. NCDase prevented apoptosis both by reducing C16-ceramide and by activation of AKT through S1P formation. Therefore, the cross-talk between sphingolipids and AKT pathway may determine hepatocyte apoptosis by TNF-alpha.
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Simons, K., & Ikonen, E. (1997) · Nature · doi:10.1038/42408 · Cited by 9,757
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Zheng, W., Kollmeyer, J., Symolon, H., Momin, A., Munter, E., Wang, E., Kelly, S., Allegood, J. C., Liu, Y., Peng, Q., et al. (2006) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2006.08.009 · Cited by 560
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Metadata
- Authors
- Osawa, Y., Uchinami, H., Bielawski, J., Schwabe, R. F., Hannun, Y. A., & Brenner, D. A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 280
- Issue
- 30
- Pages
- 27879-27887
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2029641949
- Cited by
- 221
- References
- 1
- FWCI
- 5.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- The paper
- Osawa, Y., Uchinami, H., Bielawski, J., Schwabe, R. F., Hannun, Y. A., & Brenner, D. A. (2005). Roles for C16-ceramide and Sphingosine 1-Phosphate in Regulating Hepatocyte Apoptosis in Response to Tumor Necrosis Factor-α. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m503002200
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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