Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice.
Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice.
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DOI：
10.1158/1940-6207.capr-10-0368
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Chapkin RS
中科院分区：
文献类型：
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作者：
Fan YY;Ran Q;Toyokuni S;Okazaki Y;Callaway ES;Lupton JR;Chapkin RS
线粒体功能的改变可导致氧化还原稳态的破坏，并且与异常癌细胞生长相关。锰超氧化物歧化酶（SOD 2）和谷胱甘肽过氧化物酶4（Gpx 4）是保护细胞免受氧化应激的两种最重要的抗氧化防御酶。我们以前已经表明，n-3多不饱和脂肪酸（PUFA）促进结肠细胞凋亡，结肠癌风险的标志，部分通过增强磷脂氧化。为了阐明体内氧化应激诱导的细胞凋亡的调节机制，我们喂养杂合SOD 2 Het，Gpx 4 Het和转基因Gpx 4 TG小鼠饮食含有15%玉米油（CO，富含n-6 PUFA）或3.5% CO + 11.5%鱼油（FO，富含n-3 PUFA）4周。我们的数据表明，（i）基因预沉积氧化应激促进小鼠结肠细胞凋亡（ii）n-3 PUFA对Gpx 4 Het和SOD 2 Het小鼠的细胞凋亡诱导具有相加作用;和（iii）饮食n-3 PUFA通过将细胞凋亡升高至野生型中观察到的水平，逆转氧化保护的Gpx 4 Tg小鼠的表型（对照）动物。检查结肠线粒体生物能谱的补充实验表明，相对于对照CO处理，FO喂养的小鼠表现出显著（p<0.05）增加的呼吸诱导的质子泄漏。这一发现与慢性氧化应激引起的膜电位损失一致，并支持n-3 PUFA改变线粒体代谢活性，从而增强细胞凋亡和降低结肠癌风险的论点。
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 have 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 wk. Our data show that (i) genetic pre-deposition 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 (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 is 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.