title: A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice.
abstract: BACKGROUND
  Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR(-/-) mice.
  
  
  METHODS
  Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism.
  
  
  RESULTS
  Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoyl-sphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress.
  
  
  CONCLUSIONS
  DHA regulation of hepatic SFA, MUFA, PUFA, sphingomyelin, PUFA-derived oxidized lipids and S-lactoylglutathione may explain the protective effects of DHA against WD-induced NASH in LDLR(-/-) mice.
authors.affiliation: The Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America ; The Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Depner
authors.affiliation: The Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America ; The Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Maret G
authors.initials: MG
authors.lastname: Traber
authors.affiliation: Department of Animal and Rangeland Sciences, Oregon State University, Corvallis, Oregon, United States of America ; The Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Gerd
authors.initials: G
authors.lastname: Bobe
authors.affiliation: Metabolon, Inc., Durham, North Carolina, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kensicki
authors.affiliation: United States Department of Agriculture, Agricultural Research Service, Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Bohren
authors.affiliation: Eicosanoid Core Laboratory, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Ginger
authors.initials: G
authors.lastname: Milne
authors.affiliation: The Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America ; The Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Jump
mesh_terms: D000818:Animals; D002244:Carbon / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D004731:Endotoxins / Q000097:blood; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism*; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress; D010743:Phospholipids / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics*; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D004731:Endotoxins; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D015525:Fatty Acids, Omega-3; D010743:Phospholipids; D011973:Receptors, LDL; D013109:Sphingomyelins; C033171:palmitoylsphingomyelin; D002244:Carbon