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J Lipid Research 2011 Apr;52(4):771-81. Epub 2010 Dec

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

Cheng, Y; Duan, RD; Hansen, GH; Koentgen, F; Niels-Christiansen, LL; Nilsson, A; Ohlsson, L; Zhang, Y

Gastroenterology and Nutrition Laboratory, Biomedical Center B11, Lund University, S-221 84 Lund, Sweden.

Abstract:
Alkaline sphingomyelinase (alk-SMase) hydrolyses sphingomyelin (SM) to ceramide in the gut. To evaluate the physiological importance of the enzyme, we generated alk-SMase knockout (KO) mice by the Cre-recombinase-Locus of X-over P1(Cre-LoxP) system and studied SM digestion. Both wild-type (WT) and KO mice were fed H-palmitic acid labeled SM together with milk SM by gavage. The lipids in intestinal content, intestinal tissues, serum, and liver were analyzed by TLC. In KO mice, nondigested H-SM in the intestinal content increased by 6-fold and the formation of H-ceramide decreased markedly, resulting in 98% reduction of H-ceramide/ H-SM ratio 1 h after gavage. The absorbed H-palmitic acid portion was decreased by 95%. After 3 h, a small increase in H-ceramide was identified in distal intestine in KO mice. In feces, H-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. This study provides definite proof for crucial roles of alk-SMase in SM digestion and points to possible roles in regulating mucosal growth and alkaline phosphatase function.

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