title: Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57BL/6 mice.
abstract: OBJECTIVE
  Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here, we aimed to investigate the interaction between adipose tissue and liver in NAFLD and identify potential early plasma markers that predict nonalcoholic steatohepatitis (NASH).
  
  
  METHODS
  C57Bl/6 mice were chronically fed a high-fat diet to induce NAFLD and compared with mice fed a low-fat diet. Extensive histological and phenotypical analyses coupled with a time course study of plasma proteins using multiplex assay were performed.
  
  
  RESULTS
  Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into four subgroups: low-fat low (LFL) responders displaying normal liver morphology, low-fat high (LFH) responders showing benign hepatic steatosis, high-fat low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and high fat high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared with HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodeling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin, and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin, and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ, and MIP-2, whereas insulin, TIMP-1, granulocyte chemotactic protein 2, and myeloperoxidase emerged as late markers.
  
  
  CONCLUSIONS
  Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH.
authors.affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Duval
authors.forename: Uwe
authors.initials: U
authors.lastname: Thissen
authors.forename: Shohreh
authors.initials: S
authors.lastname: Keshtkar
authors.forename: Bertrand
authors.initials: B
authors.lastname: Accart
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.forename: Mark V
authors.initials: MV
authors.lastname: Boekschoten
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
mesh_terms: D000273:Adipose Tissue / Q000503:physiopathology*; D000818:Animals; D001835:Body Weight; D018752:Diet, Fat-Restricted; D004041:Dietary Fats; D005234:Fatty Liver / Q000145:classification / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D014280:Triglycerides; D012313:RNA