by Elisa Lombardo, Cindy P. A. A. van Roomen, Gijs H. van Puijvelde, Roelof Ottenhoff, Marco van Eijk, Jan Aten, Johan Kuiper, Herman S. Overkleeft, Albert K. Groen, Arthur J. Verhoeven, Johannes M. F. G. Aerts, Florence Bietrix
The iminosugar N-(5'-adamantane-1'-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(-/-) 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. Our study demonstrates that AMP-DNM treatment is able to significantly correct pre-existing NASH, suggesting that inhibiting GSL synthesis may represent a novel strategy for the treatment of this pathology.