Glycosphingolipid synthesis inhibitor AMP.DNM lowers plasma cholesterol levels by promoting fecal cholesterol excretion without inhibiting cholesterol absorption

Abstract

Inhibition of glycosphingolipid synthesis with iminosugar N-(5’L-adamantane-1’L-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP.DNM) increases fecal neutral sterol output in mice. To investigate which pathways were involved in this increase, C57Bl/6J mice were treated with AMP.DNM and/or ezetimibe. Fecal neutral sterol output increased by threefold with combined AMP.DNM/ezetimibe treatment compared with approximately twofold increases with single treatments. Bile canulations and intestine perfusions showed that biliary cholesterol secretion and transintestinal cholesterol efflux were increased in mice receiving AMP.DNM treatment. This study indicates that AMP.DNM treatment of mice increases fecal neutral sterol by promoting biliary and intestinal cholesterol secretion without inhibiting cholesterol absorption.

Keywords:

• fecal neutral sterol
• glucosylceramide synthase
• glycosphingolipids
• hypercholesterolemia
• intestine
• reverse cholesterol transport