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PLoS One. 2013 Dec 17;8(12):e83756. doi: 10.1371/journal.pone.0083756. eCollection 2013.

A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice.

Author information

  • 1The 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.
  • 2Department 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.
  • 3Metabolon, Inc., Durham, North Carolina, United States of America.
  • 4United States Department of Agriculture, Agricultural Research Service, Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, United States of America.
  • 5Eicosanoid Core Laboratory, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

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.

CONCLUSION:

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.

PMID:
24358308
[PubMed - in process]
PMCID:
PMC3866250
Free PMC Article

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