Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice.
Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. The hyperinsulinemia that occurs as a consequence of insulin resistance is thought to be an important contributor to the development of fatty liver. We have shown that the iminosugar N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase, is a potent enhancer of insulin signaling in rodent models for insulin resistance and type 2 diabetes. The present study was designed to assess the impact of AMP-DNM on insulin levels, liver triglyceride synthesis, and gene expression profile. Treatment of ob/ob mice with AMP-DNM restored insulin signaling in the liver, corrected blood glucose values to levels found in lean mice, and decreased insulin concentration. The expression of sterol regulatory element-binding protein 1c target genes involved in fatty acid synthesis normalized. AMP-DNM treatment significantly reduced liver to body weight ratio and reversed hepatic steatosis, comprising fat as well as inflammatory markers. In addition, AMP-DNM treatment corrected to a large extent the gene expression profile of ob/ob mice livers toward the profile of lean mice.


CONCLUSIONS
Pharmacological lowering of glycosphingolipids with the iminosugar AMP-DNM is a promising approach to restore insulin signaling and improve glucose homeostasis as well as hepatic steatosis.
Bijl
Nora
N
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Sokolović
Milka
M
Vrins
Carlos
C
Langeveld
Mirjam
M
Moerland
Perry D
PD
Ottenhoff
Roelof
R
van Roomen
Cindy P A A
CP
Claessen
Nike
N
Boot
Rolf G
RG
Aten
Jan
J
Groen
Albert K
AK
Aerts
Johannes M F G
JM
van Eijk
Marco
M
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D006028:Glycosphingolipids; D007328:Insulin; C496281:N-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin; D014280:Triglycerides; D017485:1-Deoxynojirimycin; D005947:Glucose; D000218:Adamantane