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Updated: Oct 10, 2026
Saturated Fatty Acids Induce Ceramide-associated Macrophage Cell Death
Published on: October 31, 2017
Natural ceramide reverses Fas resistance of acid sphingomyelinase(-/-) hepatocytes
F Paris1, H Grassmé, A Cremesti
1Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Abstract:
The role of the second messenger ceramide in Fas-mediated death requires clarification. To address this issue, we generated hepatocytes from paired acid sphingomyelinase (ASMase; asmase)(+/+) and asmase(-/-) mice. asmase(-/-) hepatocytes, derived from 8-week-old mice, manifested normal sphingomyelin content and normal morphological, biochemical, and biologic features. Nonetheless, ASMase-deficient hepatocytes did not display rapid ceramide elevation or apoptosis in response to Jo2 anti-Fas antibody. asmase(-/-) hepatocytes were not inherently resistant to apoptosis because staurosporine, which did not induce early ceramide elevation, stimulated a normal apoptotic response. The addition of low nanomolar quantities of natural C16-ceramide, which by itself did not induce apoptosis, completely restored the apoptotic response to anti-Fas in asmase(-/-) hepatocytes. Other sphingolipids did not replace natural ceramide and restore Fas sensitivity. Overcoming resistance to Fas in asmase(-/-) hepatocytes by natural ceramide is evidence that it is the lack of ceramide and not ASMase which determines the apoptotic phenotype. The ability of natural ceramide to rescue the phenotype without reversing the genotype provides evidence that ceramide is obligate for Fas induction of apoptosis in hepatocytes.
Insights
Ceramide is essential for Fas-mediated apoptosis in hepatocytes. Acid sphingomyelinase (ASMase)-deficient cells lacking ceramide elevation showed resistance to Fas-induced death, which was restored by adding ceramide.
Area of Science:
- Cell Biology
- Biochemistry
- Immunology
Background:
- The second messenger ceramide's role in Fas-mediated apoptosis is not fully understood.
- Fas receptor activation triggers programmed cell death, a critical biological process.
Purpose of the Study:
- To investigate the necessity of ceramide elevation for Fas-mediated apoptosis in hepatocytes.
- To determine if acid sphingomyelinase (ASMase) is required for Fas-induced ceramide production and subsequent cell death.
Main Methods:
- Hepatocytes were generated from wild-type (ASMase(+/+)) and ASMase-deficient (ASMase(-/-)) mice.
- Cells were treated with anti-Fas antibody (Jo2) or staurosporine to induce apoptosis.
- Ceramide levels and apoptotic responses were measured in response to treatments.
Main Results:
- ASMase-deficient hepatocytes failed to exhibit rapid ceramide elevation or apoptosis upon anti-Fas stimulation.
- These cells retained normal apoptotic sensitivity to staurosporine, indicating no inherent resistance.
- Supplementation with natural C16-ceramide restored Fas-induced apoptosis in ASMase-deficient hepatocytes.
Conclusions:
- Ceramide elevation, not ASMase activity itself, is critical for Fas-mediated hepatocyte apoptosis.
- Ceramide acts as an obligate mediator in the Fas apoptotic signaling pathway in hepatocytes.
