Abstract
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 consistently able to absorb nutritional lipids from milk. Between postnatal days 5 and 7, severe defects in intestinal epithelial differentiation occurred accompanied by impaired intestinal uptake of nutrients. Villi of mutant mice became stunted, and enterocytes lacked brush border. The defects observed in mutant mice caused diarrhea, malabsorption, and early death. In this study, we show that GSLs are essential for enterocyte resorptive function but are primarily not for polarization; GSLs are required for intracellular vesicular transport in resorption-active intestine.
Highlights
The intestine contains high concentrations of glycosphingolipids, but their function remained unclear
This study has demonstrated that glycosphingolipids are initially not required for intestinal epithelial polarization, but they are quintessential for proper intestinal function, namely endocytic uptake of nutrients, in particular lipids, when intestine starts its activity after birth
UDP-glucose ceramide glucosyltransferase (Ugcg) f/f/VilCre Mice Lack GSLs in the Intestine of Newborn Mice—To investigate the role of GSLs for intestinal function, mice were generated in which the Ugcg gene, encoding the key enzyme Ugcg involved in the initial step of the glucosylceramide based GSL synthesis pathway, was deleted in a cellspecific manner in enterocytes by using a villin-cre recombinase transgene (Fig. 1A)
Summary
The intestine contains high concentrations of glycosphingolipids, but their function remained unclear. 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. Those mice were not consistently able to absorb nutritional lipids from milk. Glycosphingolipids and Intestinal Function in enterocytes of newborn mutant mice at postnatal day P0, the epithelial brush border had been formed regularly. This study has demonstrated that glycosphingolipids are initially not required for intestinal epithelial polarization, but they are quintessential for proper intestinal function, namely endocytic uptake of nutrients, in particular lipids, when intestine starts its activity after birth
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