Dietary oxidized n-3 PUFA induce oxidative stress and inflammation: role of intestinal absorption of 4-HHE and reactivity in intestinal cells

• Published in: Journal of lipid research 2012-10, Vol.53 (10), p.2069-2080
• Main Authors: Awada, Manar, Soulage, Christophe O., Meynier, Anne, Debard, Cyrille, Plaisancié, Pascale, Benoit, Bérengère, Picard, Grégory, Loizon, Emmanuelle, Chauvin, Marie-Agnès, Estienne, Monique, Peretti, Noël, Guichardant, Michel, Lagarde, Michel, Genot, Claude, Michalski, Marie-Caroline
• Format: Article
• Language: English
• Subjects: 4-hydroxy-2-alkenals; Aldehydes - administration & dosage; Aldehydes - pharmacokinetics; Animals; Biomarkers - metabolism; Caco-2 Cells; Diet, High-Fat; Fatty Acids, Omega-3 - metabolism; Glutathione Peroxidase - metabolism; Heat-Shock Proteins - metabolism; Humans; Inflammation - metabolism; Intestinal Absorption - physiology; Intestinal Mucosa - metabolism; intestine; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; nutrition; Oxidation-Reduction; Oxidative Stress; polyunsaturated fatty acids
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M026179

Dietary intake of long-chain n-3 PUFA is now widely advised for public health and in medical practice. However, PUFA are highly prone to oxidation, producing potentially deleterious 4-hydroxy-2-alkenals. Even so, the impact of consuming oxidized n-3 PUFA on metabolic oxidative stress and inflammation is poorly described. We therefore studied such effects and hypothesized the involvement of the intestinal absorption of 4-hydroxy-2-hexenal (4-HHE), an oxidized n-3 PUFA end-product. In vivo, four groups of mice were fed for 8 weeks high-fat diets containing moderately oxidized or unoxidized n-3 PUFA. Other mice were orally administered 4-HHE and euthanized postprandially versus baseline mice. In vitro, human intestinal Caco-2/TC7 cells were incubated with 4-hydroxy-2-alkenals. Oxidized diets increased 4-HHE plasma levels in mice (up to 5-fold, P < 0.01) compared with unoxidized diets. Oxidized diets enhanced plasma inflammatory markers and activation of nuclear factor kappaB (NF-κB) in the small intestine along with decreasing Paneth cell number (up to −19% in the duodenum). Both in vivo and in vitro, intestinal absorption of 4-HHE was associated with formation of 4-HHE-protein adducts and increased expression of glutathione peroxidase 2 (GPx2) and glucose-regulated protein 78 (GRP78). Consumption of oxidized n-3 PUFA results in 4-HHE accumulation in blood after its intestinal absorption and triggers oxidative stress and inflammation in the upper intestine.