Walli A K, Seidel D
J Clin Invest. 1984 Sep;74(3):867-79. doi: 10.1172/JCI111504.
Cholestasis is accompanied by the appearance of lipoprotein-X (LP-X) in plasma. This lipoprotein has a high content of unesterified cholesterol and phospholipids and appears to be ineffective in suppressing the enhanced hepatic cholesterogenesis of cholestasis. Its role as a possible causative factor for cholestatic hypercholesterolemia was investigated. When 125I-LP-X was injected into rats, it disappeared rapidly from the circulation. Calculated on the basis of gram wet weight, spleen took up more LP-X than liver. Prior ligation of the bile duct reduced the uptake in spleen. Experiments with isolated perfused rat liver showed that nonparenchymal cells (NPC) took up over eightfold more 125I-LP-X than hepatic parenchymal cells (PC). Incubation of PC, NPC, human lymphocyte suspensions, or fibroblast cultures with LP-X showed that NPC bound more LP-X than PC or fibroblasts. Lymphocytes took up 20-fold more LP-X than PC and the activity of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase was depressed by LP-X. Lymphocytes isolated from cholestatic patients showed low activity of this enzyme. The activity was increased by LP-X in isolated perfused livers, but suppressed in isolated microsomes. LP-X competitively inhibited the uptake of chylomicron remnants in isolated perfused livers and hepatocytes. In contrast, degradation of LDL by perfused livers, which were isolated from ethinyl estradiol-treated rats or human fibroblast cultures, remained unchanged in the presence of LP-X. The results indicate that cholesterol transported by LP-X is mainly taken up by the cells of the reticuloendothelial system. It increases the activity of hepatic HMG-CoA reductase and suppresses remnant uptake, thus emphasizing a major role of LP-X in cholestatic hypercholesterolemia.
胆汁淤积伴有血浆中脂蛋白-X（LP-X）的出现。这种脂蛋白含有高含量的未酯化胆固醇和磷脂，似乎无法有效抑制胆汁淤积时增强的肝脏胆固醇生成。研究了其作为胆汁淤积性高胆固醇血症可能致病因素的作用。当将125I-LP-X注入大鼠体内时，它迅速从循环中消失。以克湿重计算，脾脏摄取的LP-X比肝脏多。预先结扎胆管可减少脾脏的摄取。对离体灌注大鼠肝脏的实验表明，非实质细胞（NPC）摄取的125I-LP-X比肝实质细胞（PC）多八倍以上。用LP-X孵育PC、NPC、人淋巴细胞悬液或成纤维细胞培养物表明，NPC比PC或成纤维细胞结合更多的LP-X。淋巴细胞摄取的LP-X比PC多20倍，并且3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的活性被LP-X抑制。从胆汁淤积患者分离的淋巴细胞显示该酶的活性较低。在离体灌注肝脏中，LP-X可增加该酶的活性，但在离体微粒体中则抑制该酶的活性。LP-X在离体灌注肝脏和肝细胞中竞争性抑制乳糜微粒残粒的摄取。相反，从乙炔雌二醇处理的大鼠或人成纤维细胞培养物中分离的灌注肝脏对低密度脂蛋白（LDL）的降解在LP-X存在下保持不变。结果表明，LP-X转运的胆固醇主要被网状内皮系统的细胞摄取。它增加肝脏HMG-CoA还原酶的活性并抑制残粒摄取，从而强调了LP-X在胆汁淤积性高胆固醇血症中的主要作用。
