Ceramidases are key enzymes in the regulation of the cellular levels of ceramide, sphingosine, and S1P.To explore the physiological functions of ceramidases, we disrupted the gene encoding neutral ceramidase (Asah2) 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. We are currently utilizing the Asah2 null mice to determine if defective catabolism of sphingolipids alters the growth of intestinal tumors.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Nugent, Adrienne; Proia, Richard L (2017) The role of G protein-coupled receptors in lymphoid malignancies. Cell Signal 39:95-107
Proia, Richard L; Hla, Timothy (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125:1379-87
Kono, Mari; Tucker, Ana E; Tran, Jennifer et al. (2014) Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo. J Clin Invest 124:2076-86
Alexaki, Aikaterini; Gupta, Sita D; Majumder, Saurav et al. (2014) Autophagy regulates sphingolipid levels in the liver. J Lipid Res 55:2521-31
Olivera, Ana; Allende, Maria Laura; Proia, Richard L (2013) Shaping the landscape: metabolic regulation of S1P gradients. Biochim Biophys Acta 1831:193-202
Green, Jesse A; Suzuki, Kazuhiro; Cho, Bryan et al. (2011) The sphingosine 1-phosphate receptor S1P? maintains the homeostasis of germinal center B cells and promotes niche confinement. Nat Immunol 12:672-80
Allende, Maria L; Bektas, Meryem; Lee, Bridgin G et al. (2011) Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking. J Biol Chem 286:7348-58
Bektas, Meryem; Allende, Maria Laura; Lee, Bridgin G et al. (2010) Sphingosine 1-phosphate lyase deficiency disrupts lipid homeostasis in liver. J Biol Chem 285:10880-9
Allende, Maria L; Tuymetova, Galina; Lee, Bridgin G et al. (2010) S1P1 receptor directs the release of immature B cells from bone marrow into blood. J Exp Med 207:1113-24