Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice

Yang Yi Fan, Qitao Ran, Shinya Toyokuni, Yasumasa Okazaki, Evelyn S. Callaway, Joanne R. Lupton, Robert S. Chapkin

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

An alteration of mitochondrial function can result in disruption of redox homeostasis and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We had previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed heterozygous SOD2Het, Gpx4Het, and transgenic Gpx4Tg mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 weeks. Our data showed that (i) genetic predeposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4Het > SOD2Het > Wt > Gpx4Tg), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4Het and SOD2Het mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4Tg mice by elevating apoptosis to a level observed in wild-type (Wt; control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO-fed mice exhibit a significantly (P < 0.05) increased respiration-induced proton leak relative to control CO treatment. This finding was consistent with a loss of membrane potential in response to chronic oxidative stress and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk.

Original languageEnglish (US)
Pages (from-to)1267-1274
Number of pages8
JournalCancer Prevention Research
Volume4
Issue number8
DOIs
StatePublished - Aug 2011

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Unsaturated Dietary Fats
Fish Oils
Omega-3 Fatty Acids
Protons
Apoptosis
Oxidative Stress
Carbon Monoxide
phospholipid-hydroperoxide glutathione peroxidase
Colonic Neoplasms
Corn Oil
Unsaturated Fatty Acids
Membrane Potentials
Energy Metabolism
Transgenic Mice
Superoxide Dismutase
Oxidation-Reduction
Phospholipids
Respiration
Colon
Homeostasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice. / Fan, Yang Yi; Ran, Qitao; Toyokuni, Shinya; Okazaki, Yasumasa; Callaway, Evelyn S.; Lupton, Joanne R.; Chapkin, Robert S.

In: Cancer Prevention Research, Vol. 4, No. 8, 08.2011, p. 1267-1274.

Research output: Contribution to journalArticle

Fan, Yang Yi ; Ran, Qitao ; Toyokuni, Shinya ; Okazaki, Yasumasa ; Callaway, Evelyn S. ; Lupton, Joanne R. ; Chapkin, Robert S. / Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice. In: Cancer Prevention Research. 2011 ; Vol. 4, No. 8. pp. 1267-1274.
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