title: Dietary fat is a lipid source in 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD)-elicited hepatic steatosis in C57BL/6 mice.
abstract: 2,3,7,8-Tetrachlorodibenzo-ρ-dioxin (TCDD) increases fatty acid (FA) transport and FA levels resulting in hepatic steatosis in mice. Diet as a source of lipids was investigated using customized diets, stearoyl-CoA desaturase 1 (Scd1) null mice, and (14)C-oleate (18:1n9) uptake studies. C57BL/6 mice fed with 5, 10, or 15% fat or 50, 60 or 70% carbohydrate diets exhibited increased relative liver weight following gavage with 30 µg/kg TCDD for 168 h. Hepatic lipid extract analysis from mice fed with 5, 10, and 15% fat diets identified a dose-dependent increase in total FAs induced by TCDD. Mice fed with fat diet also exhibited a dose-dependent increase in the dietary essential linoleic (18:2n6) and α-linolenic (18:3n3) acids. No dose-dependent FA increase was detected on carbohydrate diets, suggesting dietary fat as a source of lipids in TCDD-induced steatosis as opposed to de novo lipogenesis. TCDD also induced oleate levels threefold in Scd1 null mice that are incapable of desaturating stearate (18:0). This is consistent with oleate representing > 90% of all monounsaturated FAs in rodent chow. Moreover, TCDD increased hepatic (14)C-oleate levels twofold in wild type and 2.4-fold in Scd1 null mice concurrent with the induction of intestinal and hepatic lipid transport genes (Slc27a, Fabp, Ldlr, Cd36, and Apob). In addition, computational scanning identified putative dioxin response elements and in vivo ChIP-chip analysis revealed regions of aryl hydrocarbon receptor (AhR) enrichment in lipid transport genes differentially regulated by TCDD. Collectively, these results suggest the AhR mediates increased uptake of dietary fats that contribute to TCDD-elicited hepatic steatosis.
authors.affiliation: Genetics Program;
authors.forename: Michelle Manente
authors.initials: MM
authors.lastname: Angrish
authors.forename: Bryan David
authors.initials: BD
authors.lastname: Mets
authors.forename: Arthur Daniel
authors.initials: AD
authors.lastname: Jones
authors.forename: Timothy Richard
authors.initials: TR
authors.lastname: Zacharewski
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage* / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D015870:Gene Expression; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004041:Dietary Fats; D000072317:Polychlorinated Dibenzodioxins