title: Metabolomic signatures in lipid-loaded HepaRGs reveal pathways involved in steatotic progression.
abstract: OBJECTIVE
  A spectrum of disorders including simple steatosis, nonalcoholic steatohepatitis, fibrosis, and cirrhosis is described by nonalcoholic fatty liver disease (NAFLD). With the increased prevalence of obesity, and consequently NAFLD, there is a need for novel therapeutics in this area. To facilitate this effort, a cellular model of hepatic steatosis was developed using HepaRG cells and the resulting biochemical alterations were determined.
  
  
  METHODS
  Using global metabolomic profiling, by means of a novel metabolite extraction procedure, the metabolic profiles in response to the saturated fatty acid palmitate, and a mixture of saturated and unsaturated fatty acids, palmitate and oleate (1:2) were examined.
  
  
  RESULTS
  We observed elevated levels of the branched chain amino acids, tricarboxylic acid cycle intermediates, sphingosine and acylcarnitines, and reduced levels of carnitine in the steatotic HepaRG model with both palmitate and palmitate:oleate treatments. In addition, elevated levels of diacylglycerols and monoacylglycerols as well as altered bile acid metabolism were selectively displayed by palmitate-induced steatotic cells.
  
  
  CONCLUSIONS
  Biochemical changes in pathways important in the transition to hepatic steatosis including insulin resistance, altered mitochondrial metabolism, and oxidative stress are revealed by this global metabolomic approach. Moreover, the utility of this in vitro model for investigating the mechanisms of steatotic progression, insulin resistance, and lipotoxicity in NAFLD was demonstrated.
authors.affiliation: Metabolon, Inc., Durham, North Carolina, USA.
authors.forename: Meredith V
authors.initials: MV
authors.lastname: Brown
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Compton
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: Kay A
authors.initials: KA
authors.lastname: Lawton
authors.forename: Bentley
authors.initials: B
authors.lastname: Cheatham
mesh_terms: D001647:Bile Acids and Salts / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D018450:Disease Progression; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000166:cytology / Q000473:pathology; D055442:Metabolome; D008928:Mitochondria / Q000378:metabolism; D050178:Monoglycerides / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D019301:Oleic Acid / Q000494:pharmacology; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D004075:Diglycerides; D007328:Insulin; D050178:Monoglycerides; D017382:Reactive Oxygen Species; D019301:Oleic Acid; D019308:Palmitic Acid