title: Lipotoxicity and steatohepatitis in an overfed mouse model for non-alcoholic fatty liver disease.
abstract: The major risk factors for non-alcoholic fatty liver disease (NAFLD) are obesity, insulin resistance and dyslipidemia. The cause for progression from the steatosis stage to the inflammatory condition (non-alcoholic steatohepatitis (NASH)) remains elusive at present. Aim of this study was to test whether the different stages of NAFLD as well as the associated metabolic abnormalities can be recreated in time in an overfed mouse model and study the mechanisms underlying the transition from steatosis to NASH. Male C57Bl/6J mice were subjected to continuous intragastric overfeeding with a high-fat liquid diet (HFLD) for different time periods. Mice fed a solid high-fat diet (HFD) ad libitum served as controls. Liver histology and metabolic characteristics of liver, white adipose tisue (WAT) and plasma were studied. Both HFD-fed and HFLD-overfed mice initially developed liver steatosis, but only the latter progressed in time to NASH. NASH coincided with obesity, hyperinsulinemia, loss of liver glycogen and hepatic endoplasmatic reticulum stress. Peroxisome proliferator-activated receptor γ (Pparγ), fibroblast growth factor 21 (Fgf21), fatty acid binding protein (Fabp) and fatty acid translocase (CD36) were induced exclusively in the livers of the HFLD-overfed mice. Inflammation, reduced adiponectin expression and altered expression of genes that influence adipogenic capacity were only observed in WAT of HFLD-overfed mice.
  
  
  CONCLUSIONS
  this dietary mouse model displays the different stages and the metabolic settings often found in human NAFLD. Lipotoxicity due to compromised adipose tissue function is likely associated with the progression to NASH, but whether this is cause or consequence remains to be established.
authors.affiliation: University of Amsterdam, Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Meibergdreef 71, 1105 BK Amsterdam, The Netherlands. i.c.gaemers@amc.uva.nl
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Gaemers
authors.forename: Jan M
authors.initials: JM
authors.lastname: Stallen
authors.forename: Cindy
authors.initials: C
authors.lastname: Kunne
authors.forename: Christian
authors.initials: C
authors.lastname: Wallner
authors.forename: Jochem
authors.initials: J
authors.lastname: van Werven
authors.forename: Aart
authors.initials: A
authors.lastname: Nederveen
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects*; D018450:Disease Progression; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006946:Hyperinsulinism / Q000209:etiology; D007249:Inflammation / Q000209:etiology; D050155:Lipogenesis; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009929:Organ Size; D044343:Overnutrition / Q000150:complications*; D047495:PPAR gamma / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D050556:Fatty Acid-Binding Proteins; D047495:PPAR gamma