Correction of liver steatosis by a hydrophobic iminosugar modulating glycosphingolipids metabolism.
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.
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Elisa
E
Lombardo
Cindy P A A
CP
van Roomen
Gijs H
GH
van Puijvelde
Roelof
R
Ottenhoff
Marco
M
van Eijk
Jan
J
Aten
Johan
J
Kuiper
Herman S
HS
Overkleeft
Albert K
AK
Groen
Arthur J
AJ
Verhoeven
Johannes M F G
JM
Aerts
Florence
F
Bietrix
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D050111:Imino Sugars / Q000737:chemistry / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000737:chemistry; D010084:Oxidation-Reduction / Q000187:drug effects; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
D000199:Actins; D053318:Apolipoprotein E3; D005227:Fatty Acids; D006028:Glycosphingolipids; D050111:Imino Sugars; D007328:Insulin; C496281:N-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin; D011973:Receptors, LDL; C052720:apolipoprotein E3 (Leidein); D017485:1-Deoxynojirimycin; D000218:Adamantane