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

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.Sphingolipids have diverse functional roles (1, 2). Complex sphingolipids such as sphingomyelin and glycosphingolipids are abundant plasma membrane constituents in plant and animal cells. Here they function as organizers of membrane structure, regulators of cell signaling, and mediators of cell-cell interactions. Simple sphingolipid metabolites that can be derived by the degradation of the complex sphingolipids, including ceramide, sphingosine, and sphingosine 1-phosphate, fulfill a different role as signaling molecules. These simple sphingolipids utilize both intracellular and extracellular targets and are potent regulators of cell growth and survival.In the sphingolipid degradative pathway, ceramidases (EC 3.5.1.23) catalyze the hydrolysis of the N-acyl group of ceramide to yield sphingosine and fatty acids. Sphingosine can then be phosphorylated by sphingosine kinase to yield sphingosine 1-phosphate. Thus, ceramidases are key regulators of sphingolipid signaling metabolites. Ceramidases have traditionally been classified according to the pH range (acid, neutral, or alkaline) that supports their optimal activity. Recently, the mammalian ceramidases have been defined more precisely by genetic and structural means, which has revealed at least four distinct enzymes.

Intestinal absorption of dietary maize glucosylceramide in lymphatic duct cannulated rats

“…Several reports have indicated that alkaline sphingomyelinase is present in the intestinal mucosa (35)(36)(37) and that the glycosylceramidase activity in the intestine is due to lactase-phlorizin hydrolase ( 38,39 ). Neutral ceramidase encoded by Asah2 is also present in the small intestine ( 40 ). We have reported that the hydrolytic activity in the small intestine toward glucosylceramide and ceramide derived from maize is consistent with the fi ndings of such activity toward mammalian-derived sphingolipids ( 26 ).…”

Selective Absorption of Dietary Sphingoid Bases from the Intestine via Efflux by P-Glycoprotein in Rats

“…Alkaline sphingomyelinase is present in the intestinal mucosa (25)(26)(27), and the glycosylceramidase activity in the intestine is due to lactase-phlorizin hydrolase (28,29). Neutral ceramidase encoded by Asah2 is also present in the small intestine (30). Previously, we investigated the absorption of dietary glucosylceramide derived from maize into the rat intestine compared with that of glucosyl-N-palmitoylsphingosine and demonstrated that the intact form of sphingadienine was absorbed into the lymph by intestinal cells after administration of maize glucosylceramide.…”

Human Meconium Contains Significant Amounts of Alkaline Sphingomyelinase, Neutral Ceramidase, and Sphingolipid Metabolites

“…The crucial role of neutral ceramidase in ceramide digestion in the gut was recently confirmed by studies on genetargeted mice lacking active neutral ceramidase 2 (17).…”