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The lipid messenger ceramide is converted to glucosylceramide by glucosylceramide synthase (GCS). In the reverse direction, non-lysosomal glucosylceramidase (GCase), also known as β-glucosidase 2 (BGD),1 cleaves the glucosyl moiety from glucosylceramide, liberating ceramide, which can be converted into sphingomyelin.2 AMP-deoxynojirimycin (AMP-dNM) is a hydrophobic derivative of dNM. It potently inhibits BGD (IC50 = 0.3 nM),3 less potently antagonizes GCS (IC50 = 25 nM),2 but only poorly inhibits other GCase isoforms. AMP-dNM has been shown to strongly suppress inflammation in a murine model of hapten-induced colitis,4 enhance insulin sensitivity in murine and rat models of insulin resistance,5 and induce sterol regulatory element-binding protein-regulated gene expression and cholesterol synthesis in Hep-G2 cells.1
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1
Bijl, N., Scheij, S., Houten, S., et al. The glucosylceramide synthase inhibitor N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin induces sterol regulatory element-binding protein-regulated gene expression and cholesterol synthesis in HepG2 cells. J Pharmacol Exp Ther 326(3) 849-855 (2008).
2
Aerts, J.M., Hollak, C., Boot, R., et al. Biochemistry of glycosphingolipid storage disorders: Implications for therapeutic intervention. Philos Trans R Soc Lond B Biol Sci 358 905-914 (2003).
3
Overkleeft, H.S., Renkema, G.H., Neele, J., et al. Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase. J Biol Chem 273(41) 26522-26527 (1998).
4
Shen, C., Bullens, D., Kasran, A., et al. Inhibition of glycolipid biosynthesis by N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin protects against the inflammatory response in hapten-induced colitis. International Immunopharmacology 4 939-951 (2004).
5
Aerts, J.M., Ottenhoff, R., Powlson, A.S., et al. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56 1341-1349 (2007).
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