title: Dietary oxidized n-3 PUFA induce oxidative stress and inflammation: role of intestinal absorption of 4-HHE and reactivity in intestinal cells.
abstract: 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.
authors.affiliation: INSA-Lyon, IMBL, F-69621 Villeurbanne, France; INRA, U1235 CarMeN laboratory, F-69621 Villeurbanne, France.
authors.forename: Manar
authors.initials: M
authors.lastname: Awada
authors.affiliation: INSA-Lyon, IMBL, F-69621 Villeurbanne, France.
authors.forename: Christophe O
authors.initials: CO
authors.lastname: Soulage
authors.affiliation: INRA, UR1268 Biopolymères Interactions Assemblages, F-44300 Nantes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Meynier
authors.affiliation: INSERM, U1060, CarMeN laboratory, F-69921 Oullins, France; and.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Debard
authors.affiliation: INRA, U1235 CarMeN laboratory, F-69621 Villeurbanne, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Plaisancié
authors.affiliation: Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Benoit
authors.affiliation: Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Picard
authors.affiliation: Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Loizon
authors.affiliation: INSERM, U1060, CarMeN laboratory, F-69921 Oullins, France; and.
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Chauvin
authors.affiliation: INRA, U1235 CarMeN laboratory, F-69621 Villeurbanne, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Estienne
authors.affiliation: Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France.
authors.forename: Noël
authors.initials: N
authors.lastname: Peretti
authors.affiliation: INSA-Lyon, IMBL, F-69621 Villeurbanne, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Guichardant
authors.affiliation: INSA-Lyon, IMBL, F-69621 Villeurbanne, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lagarde
authors.affiliation: INRA, UR1268 Biopolymères Interactions Assemblages, F-44300 Nantes, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Genot
authors.affiliation: INSA-Lyon, IMBL, F-69621 Villeurbanne, France; INRA, U1235 CarMeN laboratory, F-69621 Villeurbanne, France; Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France. Electronic address: marie-caroline.michalski@insa-lyon.fr.
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Michalski
mesh_terms: D000447:Aldehydes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018938:Caco-2 Cells; D059305:Diet, High-Fat; D000091342:Endoplasmic Reticulum Chaperone BiP; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D018384:Oxidative Stress
chemical_list: D000447:Aldehydes; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; D015525:Fatty Acids, Omega-3; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C045934:4-hydroxy-2-hexenal; D005979:Glutathione Peroxidase