Role of lipoprotein-X in the pathogenesis of cholestatic hypercholesterolemia. Uptake of lipoprotein-X and its effect on 3-hydroxy-3-methylglutaryl coenzyme A reductase and chylomicron remnant removal in human fibroblasts, lymphocytes, and in the rat.
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.
D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D002779:Cholestasis / Q000150:complications*; D002914:Chylomicrons / Q000097:blood*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000150:complications*; D007700:Kinetics; D008073:Lipoprotein-X / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012867:Skin / Q000378:metabolism; D014018:Tissue Distribution
D002914:Chylomicrons; D008073:Lipoprotein-X; D008077:Lipoproteins, LDL; D006903:Hydroxymethylglutaryl CoA Reductases