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

J Lipid Res. 2012 Oct;53(10):2069-80. doi: 10.1194/jlr.M026179. Epub 2012 Aug 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Lipid Peroxidation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidation-Reduction
  • Oxidative Stress*


  • Aldehydes
  • Biomarkers
  • Fatty Acids, Omega-3
  • Heat-Shock Proteins
  • 4-hydroxy-2-hexenal
  • Glutathione Peroxidase
  • molecular chaperone GRP78