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A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice.
PLoS One. 2013; 8(12):e83756.Plos

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.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

24358308

Citation

Depner, Christopher M., et al. "A Metabolomic Analysis of Omega-3 Fatty Acid-mediated Attenuation of Western Diet-induced Nonalcoholic Steatohepatitis in LDLR-/- Mice." PloS One, vol. 8, no. 12, 2013, pp. e83756.
Depner CM, Traber MG, Bobe G, et al. A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice. PLoS ONE. 2013;8(12):e83756.
Depner, C. M., Traber, M. G., Bobe, G., Kensicki, E., Bohren, K. M., Milne, G., & Jump, D. B. (2013). A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice. PloS One, 8(12), e83756. https://doi.org/10.1371/journal.pone.0083756
Depner CM, et al. A Metabolomic Analysis of Omega-3 Fatty Acid-mediated Attenuation of Western Diet-induced Nonalcoholic Steatohepatitis in LDLR-/- Mice. PLoS ONE. 2013;8(12):e83756. PubMed PMID: 24358308.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice. AU - Depner,Christopher M, AU - Traber,Maret G, AU - Bobe,Gerd, AU - Kensicki,Elizabeth, AU - Bohren,Kurt M, AU - Milne,Ginger, AU - Jump,Donald B, Y1 - 2013/12/17/ PY - 2013/08/27/received PY - 2013/11/07/accepted PY - 2013/12/21/entrez PY - 2013/12/21/pubmed PY - 2014/9/17/medline SP - e83756 EP - e83756 JF - PloS one JO - PLoS ONE VL - 8 IS - 12 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24358308/A_metabolomic_analysis_of_omega_3_fatty_acid_mediated_attenuation_of_western_diet_induced_nonalcoholic_steatohepatitis_in_LDLR_/__mice_ L2 - http://dx.plos.org/10.1371/journal.pone.0083756 DB - PRIME DP - Unbound Medicine ER -