Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: A study on the enzyme knockout mice.

Alkaline sphingomyelinase (alk-SMase) hydrolyses sphingomyelin (SM) to ceramide in the gut. To evaluate physiological importance of the enzyme, we generated alk-SMase knockout (KO) mice by Cre-LoxP system and studied SM digestion. Both wild type (WT) and the KO mice were fed 3H-palmitic acid labeled SM together with milk SM by gavage. The lipids in intestinal content, intestinal tissues, serum and liver were analysed by TLC. In KO mice, non-digested 3H-SM in the intestinal content increased by 6 fold and the formation of 3H-ceramide decreased markedly, resulting in 98% reduction of 3H-ceramide/3H-SM ratio 1 h after gavage. The absorbed 3H-palmitic acid portion was decreased by 95%. After three hours, a small increase in 3H-ceramide was identified in distal intestine in KO mice. In feces 3H-SM was increased by 243% and ceramide decreased by 74% in the KO mice. The KO mice also showed significantly decreased radioactivity in liver and serum. Furthermore alkaline phosphatase activity in the mucosa was reduced by 50%, and histological comparison of two female littermates preliminarily suggested mucosal hypertrophy in KO mice. The study provides definite proofs for crucial roles of alk-SMase in SM digestion and points to possible roles in regulating mucosal growth and alkaline phosphatase function.