TYPES AND AMOUNT OF DIETARY FAT AND COLON CANCER

流行病学和动物模型研究表明， 某些类型的脂肪在结肠癌的风险中起作用 发展 长期目标是了解调制 脂肪酸组成不同的脂肪的量和类型的影响 在结肠肿瘤的促进和进展中。具体而言，建议 研究膳食脂肪的种类和数量的机制， 玉米油（CO）和鲱鱼油（FO）富含omega-6和omega-3 脂肪酸，分别和混合脂质高饱和脂肪。 最近的研究表明，某些膳食脂肪的高摄入量 与次级胆汁产生的改变有关 结肠内容物中的酸、二酰基甘油（DAG）和脂肪酸 它可以进入结肠粘膜并激活几种细胞 包括蛋白激酶C（PKC）、花生四烯酸代谢和 例如ras p21。 这些生物化学和分子事件导致 以膳食脂肪的种类和量为依据， 问题研究具体而言，建议确定饮食的影响 高和低的CO和高的FO和混合脂质的生产 DAG由肠道菌群、结肠腔脂肪酸组成 （粪便）DAG、结肠粘膜和肿瘤上调和下调 PKC同工酶、环氧合酶同工酶和法呢基的调节 结肠促进和进展阶段的蛋白质转移酶 致癌作用 在5周龄时，将各组雄性F344大鼠喂食 低脂肪AIN-76 A饮食含有CO（LFCO）。 在7周龄时，各组 的动物将用每周两次的s.c.氧化偶氮甲烷剂量 (AOM)或生理盐水（媒介物），一天后，将它们 转移到含有CO（HFCO）或FO（HFF 0）的高脂肪饮食。一 组将继续LFCO饮食。 然后动物群体 在AOM或盐水处理后第1、12、36和50周处死。 处死前，将采集一周的每日粪便样本 并分析粪便DAG质量及其脂肪酸 混合物. 盲肠内容物将用于确定生产 DAG的肠道菌群。 在第1、12、14周收集结肠粘膜， 36和50以及结肠肿瘤将用于确定 PKC、环氧合酶1和2以及法尼基蛋白转移酶。 这些 用AOM处理的动物的生物化学和分子参数，或 将对生理盐水和喂食实验饮食的动物进行统计学分析， 确定差异的显著性。 希望结果 从拟议的机制研究产生的将加强 结肠癌一级和二级预防的基本原理， 饮食调节

Epidemiologic and animal model studies suggest that dietary intake of certain types of fat plays a role in the risk of colon cancer development. The long term objective is to understand the modulating effects of amount and types of fat differing in fatty acid composition in colon tumor promotion and progression. Specifically, it is proposed to investigate the mechanism(s) of types and amount of dietary fat such as corn oil (CO) and menhaden fish oil (FO) rich in omega-6 and omega-3 fatty acids, respectively and mixed lipid high in saturated fats. Recent studies indicate that high intake of certain dietary fats has been associated with an alteration in the production of secondary bile acids, diacylglycerols (DAG) and fatty acids in the colonic contents which could enter the colonic mucosa and activate several cellular events including protein kinase C (PKC), arachidonic acid metabolism and ras p21, to cite a few. These biochemical and molecular events induced by types and amount of dietary fat became a basis to conduct in-depth studies. Specifically, it is proposed to determine the effect of diets high and low in CO and high in FO and mixed lipids on the production of DAG by the gut microflora, fatty acid composition of colonic luminal (fecal) DAGs, colonic mucosal and tumor up-regulation and down- regulation of PKC isozymes, cyclooxygenase isozymes, and farnesyl protein transferase during promotion and progression stages of colon carcinogenesis. At 5 weeks of age, groups of male F344 rats will be fed low-fat AIN-76A diet containing CO (LFCO). At 7 weeks of age, groups of animals will be treated with two weekly s.c. doses of azoxymethane (AOM) or normal saline (vehicle and one day later, they will be transferred to high fat diets containing CO (HFCO) or FO (HFF0). One group will be continued on LFCO diet. Then the groups of animals will be sacrificed at weeks 1, 12, 36 and 50 after AOM or saline treatment. Prior to sacrifice, daily stool samples for one week will be collected from each animal and analyzed for fecal DAG mass and their fatty acid composition. Cecal contents will be used to determine the production of DAG by intestinal microflora. Colon mucosa harvested at weeks 1, 12, 36 and 50 and colon tumors will be used to determine the isoforms of PKC, cyclooxygenase 1 and 2, and farnesyl-protein transferase. These biochemical and molecular parameters of animals treated with AOM or saline and fed the experimental diets will be analyzed statistically to determine the significance of difference. It is hoped that the results generated from the proposed mechanistic study will strengthen the rationale for primary and secondary prevention of colon cancer through dietary modulation.