title: Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids.
abstract: 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.
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Kono
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Dreier
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Ellis
authors.forename: Maria L
authors.initials: ML
authors.lastname: Allende
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Kalkofen
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Sanders
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
mesh_terms: 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
chemical_list: 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