correction of liver steatosis by a hydrophobic iminosugar modulating glycosphingolipids metabolism修正肝脂肪变性的疏水性iminosugar调制鞘糖脂代谢.pdfVIP

Correction of Liver Steatosis by a Hydrophobic Iminosugar Modulating Glycosphingolipids Metabolism 1 1 2 1 1 Elisa Lombardo , Cindy P. A. A. van Roomen , Gijs H. van Puijvelde , Roelof Ottenhoff , Marco van Eijk , 3 2 4 5 1 Jan Aten , Johan Kuiper , Herman S. Overkleeft , Albert K. Groen , Arthur J. Verhoeven , Johannes M. F. G. Aerts1*, Florence Bietrix1 1 Departments of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 2 Division of Biopharmaceutics, Leiden/ Amsterdam Center for Drug Research (LACDR), Leiden University, Leiden, The Netherlands, 3 Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 4 Division of Biopharmaceutics, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands, 5 Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands Abstract The iminosugar N-(5 9-adamantane-19-yl-methoxy)-pentyl-1-deoxynoijirimycin (AMP-DNM), an inhibitor of glycosphingolipid (GSL) biosynthesis is known to ameliorate diabetes, insulin sensitivity and to prevent liver steatosis in ob/ob mice. Thus far the effect of GSL synthesis inhibition on pre-existing NASH has not yet been assessed. To investigate it, LDLR( 2/ 2) mice were kept on a western-type diet for 12 weeks to induce NASH. Next, the diet was continued for 6 weeks in presence or not of AMP-DNM in the diet. AMP-DNM treated mice showed less liver steatosis, inflammation and fibrosis. Induction of fatty acid beta-oxydation was observed, as well as a reduction of plasma lipids. O