Neutral Ceramidase Encoded by the Asah2 Gene Is Essential for the Intestinal Degradation of Sphingolipids

Mari Kono,Jennifer L Dreier,Jessica M Ellis,Maria L Allende,Danielle N Kalkofen,Kathleen M Sanders,Jacek Bielawski,Alicja Bielawska,Yusuf A Hannun,Richard L Proia

doi:10.1074/jbc.m508382200

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.

Highlights

Sphingolipids have diverse functional roles [1, 2]
Our findings indicate that an essential physiologic function of the neutral ceramidase is for the metabolism of dietary sphingolipids and, the regulation of bioactive ceramide and sphingosine levels in the gastrointestinal tract
Alkaline sphingomyelinase (Enpp5) [32], sphingosine kinase 1 (Sphk1), and Ceramide exists at a critical branch point in sphingolipid metabolism, utilized both as a backbone for the synthesis of complex sphingolipids and via degradation, for the generation of bioactive lipids including sphingosine and sphingosine 1-phosphate

Summary

Introduction

Sphingolipids have diverse functional roles [1, 2]. Complex sphingolipids such as sphingomyelin and glycosphingolipids are abundant plasma membrane constituents in plant and animal cells. In agreement with a previous report [11], in normal mice the Asah2 gene was found to be highly expressed in small intestine when compared with expression levels in the brain, liver, and other portions of the gastrointestinal tract, including stomach, cecum, and colon (Fig. 2A). In normal (wild-type) mice, neutral ceramidase activity was highly elevated in small intestinal mucosa compared with extracts of brain, liver, and kidney (Fig. 2B).

Results

Conclusion