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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Deoxynojirimycin / analogs & derivatives
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1-Deoxynojirimycin / chemistry
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1-Deoxynojirimycin / pharmacology
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Actins / genetics
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Actins / metabolism
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Adamantane / analogs & derivatives
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Adamantane / chemistry
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Adamantane / pharmacology
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Animals
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Apolipoprotein E3 / genetics
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Apolipoprotein E3 / metabolism
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Cell Membrane / chemistry
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Diet, High-Fat / adverse effects
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Dose-Response Relationship, Drug
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Fatty Acids / metabolism
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Fatty Liver / etiology
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Fatty Liver / genetics
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Fatty Liver / prevention & control*
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Female
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Gene Expression / drug effects
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Glycosphingolipids / antagonists & inhibitors*
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Glycosphingolipids / metabolism
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Humans
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Hydrophobic and Hydrophilic Interactions
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Imino Sugars / chemistry
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Imino Sugars / pharmacology*
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Immunohistochemistry
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Insulin / blood
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Lipid Metabolism / drug effects
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Liver / drug effects*
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Liver / metabolism
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Liver / pathology
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Mice
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Mice, Knockout
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Mice, Transgenic
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Muscle, Smooth / chemistry
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Oxidation-Reduction / drug effects
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Receptors, LDL / deficiency
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Receptors, LDL / genetics
Substances
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Actins
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Apolipoprotein E3
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Fatty Acids
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Glycosphingolipids
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Imino Sugars
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Insulin
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N-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin
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Receptors, LDL
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apolipoprotein E3 (Leidein)
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1-Deoxynojirimycin
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Adamantane
Grants and funding
Elisa Lombardo is supported by the Netherlands Heart Foundation, grant 2007B030. Marco van Eijk is supported by the Dutch Diabetes foundation, grant 2009.80.016. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.