Craven P A, DeRubertis F R
Department of Medicine, Veterans Administration Medical Center, Pittsburgh, Pennsylvania.
Gastroenterology. 1988 Sep;95(3):676-85. doi: 10.1016/s0016-5085(88)80014-3.
Some, but not all, studies have suggested that high-fat diets promote colon carcinogenesis, possibly by stimulating the proliferative activity of colonic epithelium. Both the increase in colonic excretion of bile salts and of fatty acids that occur with an increase in fat ingestion have been implicated as stimuli of epithelial proliferative activity. In this study, we examined the role of activation of protein kinase C in fatty acid-induced stimulation of colonic epithelial proliferation in the rat. Intracolonic instillation of arachidonate, linoleate, or oleate at concentrations that did not induce surface cell injury or loss increased colonic mucosal ornithine decarboxylase activity and stimulated incorporation of [3H]thymidine into mucosal deoxyribonucleic acid. The saturated fatty acid palmitate was without effect. Arachidonate, linoleate, and oleate each induced the translocation of protein kinase C activity from the soluble fraction to the membrane fraction of colonic mucosa, an index of enzyme activation. The translocation of protein kinase C induced by unsaturated fatty acids occurred both in vivo after intracolonic instillation of these agents and in vitro upon incubation of isolated colonic crypt epithelium with fatty acids. The effects of the unsaturated fatty acids on both enzyme translocation and colonic epithelial proliferative activity were suppressed by 1-(5-isoquinolinyl)-2-methylpiperazine, an inhibitor of protein kinase C activity. Unsaturated fatty acids directly stimulated soluble colonic mucosal protein kinase C activity when added to the enzyme assay mixture. This action was blocked by 1-(5-isoquinolinyl)-2-methylpiperazine. However, unsaturated fatty acids also increased the breakdown of polyphosphoinositides when added to isolated colonic epithelium. The increase in polyphosphoinositide breakdown resulted in release of diacylglycerol, an endogenous activator of protein kinase C. Thus, unsaturated fatty acids may activate protein kinase C of colonic epithelium through either a direct intracellular effect or through an action on the cell membrane. The results support a role for protein kinase C in the stimulation of colonic epithelial proliferation by unsaturated fatty acids.
一些（而非全部）研究表明，高脂饮食可能通过刺激结肠上皮的增殖活性来促进结肠癌发生。随着脂肪摄入量增加，结肠胆汁盐和脂肪酸排泄量的增加均被认为是上皮增殖活性的刺激因素。在本研究中，我们检测了蛋白激酶C激活在脂肪酸诱导的大鼠结肠上皮增殖刺激中的作用。结肠内滴注花生四烯酸、亚油酸或油酸，其浓度不会引起表面细胞损伤或丢失，可增加结肠黏膜鸟氨酸脱羧酶活性，并刺激[3H]胸腺嘧啶核苷掺入黏膜脱氧核糖核酸。饱和脂肪酸棕榈酸酯则无此作用。花生四烯酸、亚油酸和油酸均可诱导蛋白激酶C活性从结肠黏膜的可溶性部分转位至膜部分，这是酶激活的一个指标。不饱和脂肪酸诱导的蛋白激酶C转位在结肠内滴注这些试剂后在体内发生，以及在体外将分离的结肠隐窝上皮与脂肪酸孵育时也会发生。不饱和脂肪酸对酶转位和结肠上皮增殖活性的影响均被1-（5-异喹啉基）-2-甲基哌嗪抑制，这是一种蛋白激酶C活性抑制剂。当添加到酶测定混合物中时，不饱和脂肪酸直接刺激可溶性结肠黏膜蛋白激酶C活性。此作用被1-（5-异喹啉基）-2-甲基哌嗪阻断。然而，不饱和脂肪酸添加到分离的结肠上皮时也会增加多磷酸肌醇的分解。多磷酸肌醇分解的增加导致二酰基甘油的释放，二酰基甘油是蛋白激酶C的内源性激活剂。因此，不饱和脂肪酸可能通过直接的细胞内效应或通过对细胞膜的作用来激活结肠上皮的蛋白激酶C。这些结果支持蛋白激酶C在不饱和脂肪酸刺激结肠上皮增殖中发挥作用。
