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Asah1  -  N-acylsphingosine amidohydrolase 1

Mus musculus

Synonyms: 2310081N20Rik, AC, ACDase, AL022942, AU044555, ...
 
 
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Disease relevance of Asah1

 

High impact information on Asah1

  • Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death [4].
  • We have tested two hypotheses regarding the relationship between AC content and beta-adrenergic receptor (betaAR)-mediated signal transduction in cardiac myocytes [5].
  • Hepatic ceramide levels transiently increased after the reperfusion phase of the ischemic liver in mice, because of an early activation of acidic sphingomyelinase (ASMase) followed by acid ceramidase stimulation [6].
  • By contrast, AC overexpression stimulated the accrual of sphingosine [7].
  • To determine the contribution of either sphingolipid in FFA-dependent inhibition of insulin action, we generated C2C12 myotubes that constitutively overexpress acid ceramidase (AC), an enzyme that catalyzes the lysosomal conversion of ceramide to sphingosine [7].
 

Biological context of Asah1

  • Genotype analysis of over 150 offspring or embryos from heterozygous intercrosses revealed an absence of Asah1(-/-) individuals at embryonic day (E) 8.5 or later, although the ratio of wild-type to Asah1(+/-) individuals from these intercrosses was 1:2 [8].
  • Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes [8].
  • Point mutations in the gene (Asah1) encoding one ceramidase, acid ceramidase (AC), lead to the lysosomal storage disorder Farber disease (FD) [8].
  • The purified protein contained the same 13-(alpha) and 40 (beta)-kDa subunits as human acid ceramidase from natural sources, had an acidic pH optimum (4.5), and followed normal Michaelis-Menten kinetics using 14C- and BODIPY-labeled C12-ceramide as substrates [1].
  • Acid ceramidase, expressed in a recombinant SV, decreased intracellular ceramide and protected cells from apoptosis [9].
 

Anatomical context of Asah1

  • To investigate the role of AC in mammalian development, we disrupted the mouse gene Asah1 in embryonic stem cells by homologous recombination mediated insertion of an AC targeting vector into the wild-type sequence [8].
  • Uptake studies using mouse macrophages revealed rapid internalization of the acid ceramidase activity from the hamster cell media but not acid sphingomyelinase [1].
  • A fluorescence-based assay system was developed to determine AC enzymatic activity, and transfection of COS-1 cells with the full-length mouse cDNA led to increased AC activity, demonstrating its functionality [10].
  • Of the tissues studied, the highest AC activity and mRNA levels were found in the kidney, followed by the brain; almost no AC activity or mRNA was found in the testis or skeletal muscle [10].
  • Neutral/alkaline and acid ceramidase activities are actively released by murine endothelial cells [11].
 

Associations of Asah1 with chemical compounds

 

Other interactions of Asah1

 

Analytical, diagnostic and therapeutic context of Asah1

  • Northern blot analysis showed that AC expression was turned on early in development, by E7.0, and continued through at least E17 [8].
  • We have characterized a 1931-bp putative promoter region of the murine AC gene by Luciferase reporter assays, electrophoretic mobility shift assays, and mutational analysis [12].

References

  1. Purification and characterization of recombinant, human acid ceramidase. Catalytic reactions and interactions with acid sphingomyelinase. He, X., Okino, N., Dhami, R., Dagan, A., Gatt, S., Schulze, H., Sandhoff, K., Schuchman, E.H. J. Biol. Chem. (2003) [Pubmed]
  2. Homozygous K5Cre transgenic mice have wavy hair and accelerated malignant progression in a murine model of skin carcinogenesis. Chan, E.L., Peace, B.E., Toney, K., Kader, S.A., Pathrose, P., Collins, M.H., Waltz, S.E. Mol. Carcinog. (2007) [Pubmed]
  3. Specific and sensitive assay for alkaline and neutral ceramidases involving C12-NBD-ceramide. Tani, M., Okino, N., Mitsutake, S., Ito, M. J. Biochem. (1999) [Pubmed]
  4. Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death. Strelow, A., Bernardo, K., Adam-Klages, S., Linke, T., Sandhoff, K., Krönke, M., Adam, D. J. Exp. Med. (2000) [Pubmed]
  5. Increased expression of adenylylcyclase type VI proportionately increases beta-adrenergic receptor-stimulated production of cAMP in neonatal rat cardiac myocytes. Gao, M., Ping, P., Post, S., Insel, P.A., Tang, R., Hammond, H.K. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  6. Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Llacuna, L., Marí, M., Garcia-Ruiz, C., Fernandez-Checa, J.C., Morales, A. Hepatology (2006) [Pubmed]
  7. Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling. Chavez, J.A., Holland, W.L., Bär, J., Sandhoff, K., Summers, S.A. J. Biol. Chem. (2005) [Pubmed]
  8. Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes. Li, C.M., Park, J.H., Simonaro, C.M., He, X., Gordon, R.E., Friedman, A.H., Ehleiter, D., Paris, F., Manova, K., Hepbildikler, S., Fuks, Z., Sandhoff, K., Kolesnick, R., Schuchman, E.H., Hepbiloikler, S. Genomics (2002) [Pubmed]
  9. Sindbis virus entry into cells triggers apoptosis by activating sphingomyelinase, leading to the release of ceramide. Jan, J.T., Chatterjee, S., Griffin, D.E. J. Virol. (2000) [Pubmed]
  10. Cloning and characterization of the full-length cDNA and genomic sequences encoding murine acid ceramidase. Li, C.M., Hong, S.B., Kopal, G., He, X., Linke, T., Hou, W.S., Koch, J., Gatt, S., Sandhoff, K., Schuchman, E.H. Genomics (1998) [Pubmed]
  11. Neutral/alkaline and acid ceramidase activities are actively released by murine endothelial cells. Romiti, E., Meacci, E., Tani, M., Nuti, F., Farnararo, M., Ito, M., Bruni, P. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  12. KLF6 is one transcription factor involved in regulating acid ceramidase gene expression. Park, J.H., Eliyahu, E., Narla, G., DiFeo, A., Martignetti, J.A., Schuchman, E.H. Biochim. Biophys. Acta (2005) [Pubmed]
  13. Ceramide mediates tumor-induced dendritic cell apoptosis. Kanto, T., Kalinski, P., Hunter, O.C., Lotze, M.T., Amoscato, A.A. J. Immunol. (2001) [Pubmed]
  14. Oxymetholone: II. Evaluation in the Tg-AC transgenic mouse model for detection of carcinogens. Holden, H.E., Stoll, R.E., Blanchard, K.T. Toxicologic pathology. (1999) [Pubmed]
  15. Acid and neutral sphingomyelinase, ceramide synthase, and acid ceramidase activities in cutaneous aging. Jensen, J.M., Förl, M., Winoto-Morbach, S., Seite, S., Schunck, M., Proksch, E., Schütze, S. Exp. Dermatol. (2005) [Pubmed]
  16. Ceramide mediates caspase-independent programmed cell death. Thon, L., Möhlig, H., Mathieu, S., Lange, A., Bulanova, E., Winoto-Morbach, S., Schütze, S., Bulfone-Paus, S., Adam, D. FASEB J. (2005) [Pubmed]
 
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