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Nutrition and Disease

Proapoptotic Effects of Dietary (n-3) Fatty Acids Are Enhanced in Colonocytes of Manganese-Dependent Superoxide Dismutase Knockout Mice^1–3,

⁴ Program in Integrative Nutrition and Complex Diseases, ⁵ Department of Veterinary Pathobiology, ⁶ Department of Veterinary Physiology and Pharmacology, ⁷ Department of Statistics, and ⁸ Center for Environmental and Rural Health, Texas A&M University, College Station, TX 77843; ⁹ Departments of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan; and ¹⁰ Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, R3C 3P4, Canada

We recently demonstrated that (n-3) PUFA trigger the induction of apoptosis in the colon by enhancing phospholipid oxidation and mitochondrial Ca²⁺ accumulation. To further elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, a 2 x 2 experiment was designed using both wild type (control) and manganese-dependent superoxide dismutase (SOD2) heterozygous knockout mice (SOD2^+/–), which exhibit increased mitochondrial oxidative stress. Mice were fed diets differing only in the type of fat [corn oil or fish oil containing (n-3) PUFA] at 15% by weight for 4 wk. Dietary (n-3) PUFA treatment enhanced (22%) apoptosis in colonic crypts. In addition, SOD2 haploinsufficiency enhanced (20%) apoptosis, which was further increased (36%) by (n-3) PUFA feeding. Dietary lipid source and genotype interactively modulated nitrotyrosine levels (P = 0.027) and inflammation (P = 0.032). These findings demonstrate that the proapoptotic effects of (n-3) PUFA are enhanced in oxidatively stressed SOD2^+/– mice. Thus, (n-3) PUFA appear to promote an oxidation-reduction imbalance in the intestine, which may directly or indirectly trigger apoptosis and thereby reduce colon cancer risk.

^* To whom correspondence should be addressed. E-mail: r-chapkin{at}tamu.edu.

Manuscript received 23 February 2009. Initial review completed 15 March 2009. Revision accepted 17 April 2009.

Published online 20 May 2009.