Experimental analysis of inhibitory effect of n-3 polyunsaturated fatty acid on cholesterol gallstone.

在过去的50年里，胆固醇(CH)胆结石在日本的发病率急剧上升，而在此期间，鱼油或n-3多不饱和脂肪酸(PUFA)的摄入量急剧下降。我们的目的是在体内和体外阐明我们的假设，即二十碳五烯酸(EPA)，一种n-3多不饱和脂肪酸，可能对胆结石有预防作用。将EPA与其他脂肪酸或苯扎贝特在喂食高胆固醇饮食的仓鼠中的效果进行了比较。结果表明，在多种脂肪酸中，只有EPA能抑制金黄地鼠胆碱结晶和胆结石形成。伴随而来的是胆汁磷脂总浓度的增加和脂肪酸组成的改变(EPA增加，亚油酸和花生四烯酸减少)。在体外进一步研究了胆汁脂质的这些变化与预防效果之间的关系。在模型胆汁系统中，含有EPA(16：0~20：5PC)、亚油酸(16：0~18：2PC)或花生四烯酸(16：0~20：4PC)的磷脂酰胆碱(PC)的增加均可降低囊泡CH的饱和度，并同样对CH结晶产生明显的抑制作用，且呈剂量依赖关系。这些影响显然比胆汁酸更强。最后，在胆囊上皮细胞培养体系中，EPA显著抑制花生四烯酸诱导的粘液糖蛋白分泌。EPA对两个关键致病因子(胆汁结晶和粘液糖蛋白分泌)的双重抑制作用提示n-3多不饱和脂肪酸在胆结石的形成和预防中起重要作用。

The incidence of cholesterol (CH) gallstone in Japan has dramatically increased in the past 50 years, during which intake of fish oil or n-3 polyunsaturated fatty acids (PUFA) has sharply declined. We aimed to clarify both in vivo and in vitro our hypothesis that eicosapentaenoic acid (EPA), a n-3 PUFA,might have a preventive effect on CH gallstone. The effect of EPA was compared with other fatty acids or bezafibrate in hamsters fed CH-rich diet. It was revealed that among various fatty acids only EPA inhibits the CH crystallization and gallstone formation in the hamster. This was accompanied by both increased total concentration and altered fatty acid composition (an increased EPA and decreased linoleic acid and arachidonic acid) of biliary phospholipids. How these changes in biliary lipids relate to the preventive effects was further studied in vitro. In the model bile system, increases in phosphatidylcholine (PC) that contains either EPA (16 : 0-20 : 5 PC), linoleic acid (16 : 0-18 : 2 PC), or arachidonic acid (16 : 0-20 : 4 PC) all decreased the vesicular CH saturation and similarly exerted potent and dose-dependent inhibitory effect on CH crystallization. These effects were clearly stronger than bile acids. Finally, in a culture system of gallbladder epithelia, EPA significantly inhibited the arachidonic acid-induced mucus glycoprotein secretion. The dual inhibitory effects of EPA on the two key pathogenetic factors (CH crystallization and mucus glycoprotein secretion) suggest critical roles of the n-3 PUFA in the formation and prevention of CH gallstone disease.