Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Liver Int. 2010 Jul;30(6):887-97. doi: 10.1111/j.1478-3231.2010.02230.x. Epub 2010 Apr 8.
BACKGROUND/AIMS: Receptor-mediated endocytosis is a critical cellular mechanism for the uptake of lipoprotein cholesterol in the liver. Because Niemann-Pick C1 (NPC1) protein is a key component for the intracellular distribution of cholesterol originating from lipoprotein endocytosis, it may play an important role in controlling biliary cholesterol secretion and gallstone formation induced by a lithogenic diet.
We studied biliary cholesterol secretion, gallbladder lipid composition and gallstone formation in NPC1-deficient mice fed a low-fat lithogenic diet (1.5% cholesterol and 0.5% cholic acid) compared with control animals under the same diet.
The lipid secretion response to the lithogenic diet was impaired in NPC1 (-/-) mice, leading to a decreased cholesterol output and an increased hepatic cholesterol concentration compared with the lithogenic diet-fed wild-type mice. A decreased cholesterol saturation index was found in the gallbladder bile of NPC1 (+/-) and (-/-) mice after lithogenic diet feeding. Consequently, mice with a partial or a total deficiency of NPC1 had a drastically lower frequency of gallbladder cholesterol crystals and a reduced prevalence of gallstones.
Hepatic NPC1 expression is an important factor for regulating the biliary secretion of diet-derived cholesterol as well as for diet-induced cholesterol gallstone formation in mice.
背景/目的：受体介导的内吞作用是肝脏摄取脂蛋白胆固醇的关键细胞机制。由于尼曼-匹克 C1（NPC1）蛋白是胆固醇从脂蛋白内吞作用起源的细胞内分布的关键组成部分，它可能在控制由致石饮食引起的胆汁胆固醇分泌和胆结石形成中发挥重要作用。
我们研究了 NPC1 缺陷型小鼠（喂食低脂肪致石饮食（1.5%胆固醇和 0.5%胆酸））与相同饮食下的对照动物相比，胆汁胆固醇分泌、胆囊脂质组成和胆结石形成的情况。
脂质分泌对致石饮食的反应在 NPC1（-/-）小鼠中受损，导致与致石饮食喂养的野生型小鼠相比，胆固醇输出减少和肝脏胆固醇浓度增加。在致石饮食喂养后，NPC1（+/-）和（-/-）小鼠的胆囊胆汁中胆固醇饱和度指数降低。因此，NPC1 部分或完全缺乏的小鼠胆囊胆固醇晶体的频率明显降低，胆结石的患病率降低。
肝 NPC1 表达是调节胆汁中饮食来源胆固醇分泌以及调节小鼠饮食诱导胆固醇胆结石形成的重要因素。
