Sphingolipid Biology of Cancer

神经酰胺酶是调节神经酰胺、鞘氨醇和S1P细胞水平的关键酶。为了探索神经酰胺酶的生理功能，我们破坏了小鼠中性神经酰胺酶（Asah2）的编码基因。Asah2缺失小鼠寿命正常，组织中总神经酰胺水平未出现明显异常或重大改变。asah2编码的中性神经酰胺酶在沿着刷状边界的小肠中高度表达，表明中性神经酰胺酶可能参与了膳食鞘脂消化的途径。事实上，Asah2缺失的小鼠缺乏神经酰胺的肠道降解。由此可见，asah2编码的中性神经酰胺酶是膳食鞘脂分解代谢的关键酶，调控肠道内生物活性鞘脂代谢物的水平。我们目前正在利用Asah2缺失小鼠来确定鞘脂代谢缺陷是否会改变肠道肿瘤的生长。

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.