Correction of liver steatosis by a hydrophobic iminosugar modulating glycosphingolipids metabolism.

Abstract

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 7 Issue 10 Pg. e38520 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23056165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Apolipoprotein E3
• Fatty Acids
• Glycosphingolipids
• Imino Sugars
• Insulin
• N-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin
• Receptors, LDL
• apolipoprotein E3 (Leidein)
• 1-Deoxynojirimycin
• Adamantane

Topics

• 1-Deoxynojirimycin (analogs & derivatives, chemistry, pharmacology)
• Actins (genetics, metabolism)
• Adamantane (analogs & derivatives, chemistry, pharmacology)
• Animals
• Apolipoprotein E3 (genetics, metabolism)
• Cell Membrane (chemistry, drug effects, metabolism)
• Diet, High-Fat (adverse effects)
• Dose-Response Relationship, Drug
• Fatty Acids (metabolism)
• Fatty Liver (etiology, genetics, prevention & control)
• Female
• Gene Expression (drug effects)
• Glycosphingolipids (antagonists & inhibitors, metabolism)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Imino Sugars (chemistry, pharmacology)
• Immunohistochemistry
• Insulin (blood)
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism, pathology)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Muscle, Smooth (chemistry)
• Oxidation-Reduction (drug effects)
• Receptors, LDL (deficiency, genetics)