title: Lipidomic Evaluation of Aryl Hydrocarbon Receptor-Mediated Hepatic Steatosis in Male and Female Mice Elicited by 2,3,7,8-Tetrachlorodibenzo-p-dioxin.
abstract: The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic steatosis mediated by the aryl hydrocarbon receptor. To further characterize TCDD-elicited hepatic lipid accumulation, mice were gavaged with TCDD every 4 days for 28 days. Liver samples were examined using untargeted lipidomics with structural confirmation of lipid species by targeted high-resolution MS/MS, and data were integrated with complementary RNA-Seq analyses. Approximately 936 unique spectral features were detected, of which 379 were confirmed as unique lipid species. Both male and female samples exhibited similar qualitative changes (lipid species) but differed in quantitative changes. A shift to higher mass lipid species was observed, indicative of increased free fatty acid (FFA) packaging. For example, of the 13 lipid classes examined, triglycerides increased from 46 to 48% of total lipids to 68-83% in TCDD treated animals. Hepatic cholesterol esters increased 11.3-fold in male mice with moieties consisting largely of dietary fatty acids (FAs) (i.e., linolenate, palmitate, and oleate). Phosphatidylserines, phosphatidylethanolamines, phosphatidic acids, and cardiolipins decreased 4.1-, 5.0-, 5.4- and 7.4-fold, respectively, while ceramides increased 6.6-fold. Accordingly, the integration of lipidomic data with differential gene expression associated with lipid metabolism suggests that in addition to the repression of de novo fatty acid synthesis and β-oxidation, TCDD also increased hepatic uptake and packaging of lipids, while inhibiting VLDL secretion, consistent with hepatic fat accumulation and the progression to steatohepatitis with fibrosis.
authors.affiliation: Biochemistry & Molecular Biology, Institute for Integrative Toxicology, Michigan State University , East Lansing, Michigan 48824, United States.
authors.forename: Rance
authors.identifier: 0000-0002-6822-4962
authors.initials: R
authors.lastname: Nault
authors.affiliation: Biochemistry & Molecular Biology, Institute for Integrative Toxicology, Michigan State University , East Lansing, Michigan 48824, United States.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Fader
authors.affiliation: Department of Physiology, Michigan State University , East Lansing, Michigan 48824, United States.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Lydic
authors.affiliation: Biochemistry & Molecular Biology, Institute for Integrative Toxicology, Michigan State University , East Lansing, Michigan 48824, United States.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D005227:Fatty Acids / Q000032:analysis; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010712:Phosphatidic Acids / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D014280:Triglycerides / Q000032:analysis / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D002518:Ceramides; D005227:Fatty Acids; D008079:Lipoproteins, VLDL; D010712:Phosphatidic Acids; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014280:Triglycerides; D002784:Cholesterol