Glycosphingolipids are required for intestinal lipid uptake

Background: The intestine contains high concentrations of glycosphingolipids, but their function remained unclear. Results: In newborn mice lacking glycosphingolipids, intestinal epithelia were indistinguishable from control littermates. However, a few days after birth, severe defects in epithelial differentiation occurred. Conclusion: Glycosphingolipid expression in the intestinal epithelium is quintessential for maintenance of resorptive function. Significance: Glycosphingolipids are essential for enterocyte function but primarily not for brush border formation. SUMMARY Glycosphingolipids (GSLs) constitute major components of enterocytes and were hypothesized to be potentially important for intestinal epithelial polarization. The enzyme UDP-glucose ceramide glucosyltransferase (Ugcg) catalyzes the initial step of GSL-biosynthesis. Newborn-and adult mice with enterocyte specific genetic deletion of the gene Ugcg were generated. In newborn mutants lacking GSLs at day P0, intestinal epithelia were indistinguishable from those in control littermates displaying an intact polarization with regular brush border. However, those mice were not able to absorb nutritional lipids from milk regularly. Between postnatal days 5 to 7 severe defects in intestinal epithelial differentiation occurred accompanied with impaired intestinal uptake of nutrients. Villi of mutant mice became stunted and enterocytes lacked brush border. The defects observed in mutant mice caused diarrhoea, malabsoption, and early death. In the present study we show that GSLs are essential for enterocyte resorptive function but primarily not for polarization; GSLs are required for intracellular vesicular transport in resorption-active intestine. The intestine is the principal organ for digestion and absorption of nutrients. In the small intestine, enterocytes-columnar epithelial cells-cover the surfaces of villi, themselves containing thousands of densely packed apical microvilli which further amplify the surface area for absorption of nutrients. Glycosphingolipids (GSLs) are major constituents of enterocytes (1). Due to their high enterocytic expression, GSLs might be involved in several cellular processes in polarized intestinal epithelia. It could be shown that GSLs are integral constituents of lipid microdomains which seem to play important roles in membrane organization (2) and in endocytosis (3) of nutrients. In addition, GSLs might influence the biosynthesis (4) and intracellular transport of proteins (5). GSLs have been described to influence membrane receptors such as the insulin and EGF receptor (6-9). The structural relevance of GSL synthesis in the intestine could be demonstrated in C. elegans mutants with significantly decreased glucosylceramide-based GSLs. Worms devoid of GSLs showed a pronounced growth arrest. The defect could be revoked by reexpression of glucosylceramide synthase in the digestive tract (10). This study highlighted the importance of intestinal GSLs while …