Holzbach R T, Corbusier C, Marsh M, Naito H K
J Lab Clin Med. 1976 Jun;87(6):987-98.
The rapid induction of cholesterol cholelithiasis in a new experimental model, the prairie dog, has recently been reported by two groups. In this model they were able to induce gallstones in as brief a period as 2 weeks, using a 1.2 per cent cholesterol diet. This unprecedented time intensity or telescoping of the induction process provided a unique opportunity for observation of physicochemical changes occurring rapidly over a short period of time and to correlate these with degree of biliary cholesterol saturation. To make such observations, 97 adult male and female prairie dogs were used in the present study. Seventy-two were fed the high cholesterol diet and sacrificed at intervals over a 14-day period; the remaining 25 were used as controls. The primary objective of this work was to determine whether or not there was any relationship between the in vivo events induced in prairie dog bile and our recently reported detailed observations of cholesterol precipitation phenomena in synthetic bile analogs. In these studies, solutions of physiologically relevant composition were constructed, which, when plotted according to convention on a tri-linear graph, fell within the zone of metastable or suspended supersaturation. These solutions revealed a consistent and previously undescribed liquid crystal to solid crystal phase transition during their approach to equilibrium at 37 degrees C. The in vivo studies of prairie dog bile following rapid induction of supersaturation revealed identical changes. At first, the supersaturated biles were isotropic followed by a period of turbidity and invariable formation of mesophase. After a few days, the liquid crystals decreased and solid cholesterol crystallites appeared. The most striking aspect of these observations is that the in vitro work has now predicted not only static, but dynamic processes as well, with respect to cholesterol precipitation beginning with the metastably supersaturated state and eventuating in gallstone formation. Ancillary new findings, resulting from the high cholesterol diet, included the induction of human-like hyper-beta-lipoproteinemia and rapid hepatocyte degranulation shown by electron microscopy.
最近有两个研究小组报告了在一种新的实验模型——草原犬鼠中快速诱导胆固醇性胆结石的情况。在这个模型中，他们使用1.2%的胆固醇饮食，能够在短短2周内诱导出胆结石。这种前所未有的诱导过程的时间强度或时间压缩，为观察在短时间内迅速发生的物理化学变化，并将这些变化与胆汁胆固醇饱和度程度相关联，提供了一个独特的机会。为了进行这样的观察，本研究使用了97只成年雄性和雌性草原犬鼠。72只喂食高胆固醇饮食，并在14天内定期处死；其余25只作为对照。这项工作的主要目的是确定草原犬鼠胆汁中诱导的体内事件与我们最近报告的关于合成胆汁类似物中胆固醇沉淀现象的详细观察之间是否存在任何关系。在这些研究中，构建了具有生理相关成分的溶液，当按照惯例绘制在三线图上时，这些溶液落在亚稳或悬浮过饱和区域内。这些溶液在37℃接近平衡的过程中显示出一致的、以前未描述过的液晶到固晶的相变。快速诱导过饱和后对草原犬鼠胆汁的体内研究显示了相同的变化。起初，过饱和胆汁是各向同性的，随后是一段时间的浑浊和中间相的形成。几天后，液晶减少，固态胆固醇微晶出现。这些观察中最引人注目的方面是，现在体外研究不仅预测了静态过程，而且还预测了动态过程，即关于从亚稳过饱和状态开始并最终形成胆结石的胆固醇沉淀过程。高胆固醇饮食产生的辅助新发现包括诱导出类似人类的高β脂蛋白血症，以及电子显微镜显示的肝细胞快速脱颗粒。
