Natural ceramide reverses Fas resistance of acid sphingomyelinase -/- hepatocytes Journal Article

Authors: Paris, F.; Grassmé, H.; Cremesti, A.; Zager, J.; Fong, Y.; Haimovitz-Friedman, A.; Fuks, Z.; Gulbins, E.; Kolesnick, R.
Article Title: Natural ceramide reverses Fas resistance of acid sphingomyelinase -/- hepatocytes
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.
Keywords: controlled study; unclassified drug; nonhuman; protein function; proteins; animal cell; mouse; phenotype; animal; mouse mutant; animals; mice; mice, knockout; cells, cultured; hepatocytes; cell structure; apoptosis; genes; fas antigen; enzymology; mice, inbred c57bl; morphology; physiology; c57bl mouse; animalia; monoclonal antibody; cell culture; gene induction; organic acids; liver cell; biochemistry; ceramide; ceramides; sphingomyelin phosphodiesterase; second messenger; lipid composition; antigens, cd95; staurosporine; acid sphingomyelinase 1; acid sphingomyelinase-1; priority journal; article; fas antibody; monoclonal antibody jo2
Journal Title: Journal of Biological Chemistry
Volume: 276
Issue: 11
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2001-03-16
Start Page: 8297
End Page: 8305
Language: English
DOI: 10.1074/jbc.M008732200
PUBMED: 11096096
PROVIDER: scopus
Notes: Export Date: 21 May 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Zvi Fuks
    393 Fuks
  2. Francois Paris
    19 Paris
  3. Jonathan Zager
    15 Zager
  4. Yuman Fong
    772 Fong
  5. Richard N Kolesnick
    264 Kolesnick