Hepatic Oxylipin Profiles in Obese Rats: Effect of Antioxidant Supplementation

Abstract

Obesity induces biochemical changes in lipid metabolism. The extent to which enzymatic and non‐enzymatic lipid (per)oxidation products, oxylipins, are altered by obesity is of great interest. Conflicting data exist regarding oxidative damage to lipids in obesity. We investigated the extent to which antioxidants altered hepatic oxylipin profiles in the context of obesity in order to define pathways sensitive to obesity vs antioxidants. Obese‐prone rats (4 wks old) were fed either a control, low‐fat diet (LF; 10% en from fat), a high‐fat diet (HF, 45% en from fat), or a high‐fat diet with supplemented vitamin C and vitamin E (HF‐CE) for 16 wks. Animals fed the high‐fat diet with and without antioxidants accrued more fat tissue than the LF animals and were insulin resistant. Analysis of hepatic oxylipins demonstrated distinct effects resulting from obesity versus antioxidant supplementation. Measures of oxidative damage to lipids, F2‐isoprostanes and 9‐hydroxyeicosatetraenoate (9‐HETE), were not elevated by obesity, but were reduced by antioxidant supplementation. Similar results were observed with the lipoxygenase products, Lipoxin A4, 8,15‐dihydroxyETE, and 5,15‐dihydroxyETE. Conversely, obesity, with and without antioxidant supplementation, increased epoxy products of linoleic and alpha‐linolenic acids, derived through cytochrome P450 (CYP450), activity while causing a decrease in the resulting dihydroxy epoxide hydrolase metabolites. These data indicate that (1) oxidative damage to hepatic lipids is not an absolute corollary of obesity, (2) antioxidant supplementation can decrease lipoxygenase pathway activity, and (3) obesity modifies hepatic CYP450‐mediated fatty acid metabolism.