title: Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nora
authors.initials: N
authors.lastname: Bijl
authors.forename: Milka
authors.initials: M
authors.lastname: Sokolović
authors.forename: Carlos
authors.initials: C
authors.lastname: Vrins
authors.forename: Mirjam
authors.initials: M
authors.lastname: Langeveld
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.forename: Roelof
authors.initials: R
authors.lastname: Ottenhoff
authors.forename: Cindy P A A
authors.initials: CP
authors.lastname: van Roomen
authors.forename: Nike
authors.initials: N
authors.lastname: Claessen
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.forename: Jan
authors.initials: J
authors.lastname: Aten
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Marco
authors.initials: M
authors.lastname: van Eijk
mesh_terms: 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
chemical_list: D006028:Glycosphingolipids; D007328:Insulin; C496281:N-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin; D014280:Triglycerides; D017485:1-Deoxynojirimycin; D005947:Glucose; D000218:Adamantane