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.