Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids.
Complex sphingolipids are abundant as eukaryotic cell membrane components, whereas their metabolites, in particular ceramide, sphingosine, and sphingosine 1-phosphate, are involved in diverse cell signaling processes. In mammals, degradation of ceramide by ceramidase yields sphingosine, which is phosphorylated by the action of sphingosine kinase to generate sphingosine 1-phosphate. Therefore, ceramidases are key enzymes in the regulation of the cellular levels of ceramide, sphingosine, and sphingosine 1-phosphate. To explore the physiological functions of a neutral ceramidase with diverse cellular locations, we disrupted the Asah2 gene in mice. Asah2 null mice have a normal life span and do not show obvious abnormalities or major alterations in total ceramide levels in tissues. The Asah2-encoded neutral ceramidase is highly expressed in the small intestine along the brush border, suggesting that the neutral ceramidase may be involved in a pathway for the digestion of dietary sphingolipids. Indeed, Asah2 null mice were deficient in the intestinal degradation of ceramide. Thus, the results indicate that the Asah2-encoded neutral ceramidase is a key enzyme for the catabolism of dietary sphingolipids and regulates the levels of bioactive sphingolipid metabolites in the intestinal tract.
Kono
Mari
M
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Dreier
Jennifer L
JL
Ellis
Jessica M
JM
Allende
Maria L
ML
Kalkofen
Danielle N
DN
Sanders
Kathleen M
KM
Bielawski
Jacek
J
Bielawska
Alicja
A
Hannun
Yusuf A
YA
Proia
Richard L
RL
D000483:Alleles; D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D055572:Ceramidases; D002518:Ceramides / Q000737:chemistry / Q000378:metabolism; D002853:Chromatography, Liquid; D005822:Genetic Vectors; D006579:Heterozygote; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008246:Lysophospholipids / Q000737:chemistry; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D055576:Neutral Ceramidase; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D021241:Spectrometry, Mass, Electrospray Ionization; D013107:Sphingolipids / Q000737:chemistry / Q000378:metabolism; D013109:Sphingomyelins / Q000737:chemistry; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry; D013997:Time Factors; D014018:Tissue Distribution; D000099157:Sphingosine Kinase
D000581:Amidohydrolases; D055572:Ceramidases; D002518:Ceramides; D008246:Lysophospholipids; D055576:Neutral Ceramidase; D017853:Phosphotransferases (Alcohol Group Acceptor); D013107:Sphingolipids; D013109:Sphingomyelins; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C526747:Asah2 protein, mouse