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

在过去的50年中，日本胆固醇（CH）胆结石的发病率急剧增加，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。我们的目的是澄清在体内和体外我们的假设，二十碳五烯酸（EPA），n-3多不饱和脂肪酸，可能有预防作用的CH胆结石。EPA的效果进行了比较，其他脂肪酸或苯扎贝特在仓鼠喂CH丰富的饮食。结果表明，在各种脂肪酸中，只有EPA抑制仓鼠胆固醇结晶和胆结石形成。这伴随着胆汁磷脂的总浓度增加和脂肪酸组成改变（EPA增加，亚油酸和花生四烯酸减少）。胆汁脂质的这些变化如何与预防作用有关，将在体外进一步研究。在模型胆汁系统中，含有EPA（16：0-20：5 PC）、亚油酸（16：0-18：2 PC）或花生四烯酸（16：0-20：4 PC）的磷脂酰胆碱（PC）的增加均降低囊泡CH饱和度，并对CH结晶产生类似的强效和剂量依赖性抑制作用。这些效果明显比胆汁酸强。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对两个关键致病因素（CH结晶和粘液糖蛋白分泌）的双重抑制作用表明n-3 PUFA在CH胆石病的形成和预防中起关键作用。

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.