Polymyxin B enhances low density lipoprotein catabolism in hepatic and extrahepatic cells.
We investigated the effects of polymyxin B (PMB), an antibiotic that binds to endotoxins, on the uptake and degradation of low density lipoproteins (LDLs) in HepG2 cells, a highly differentiated human hepatoma cell line. The results showed that PMB very effectively enhanced the binding, internalization, and degradation of LDL in HepG2 cells. The PMB-mediated enhancement of LDL uptake was not dependent on the LDL receptor-mediated pathway, as blockage of the LDL receptor by use of a monoclonal anti-LDL receptor antibody had no effect on the PMB-mediated cellular processing of LDL and PMB-mediated enhancement of LDL uptake did not cause an increase in cholesterol esterification. In addition, chloroquine and colchicine, which inhibit lysosomal degradation and cellular endocytosis, respectively, diminished PMB-enhanced degradation of LDL, indicating that PMB mediates uptake through a pathway similar to the LDL receptor-mediated pathway. The PMB-mediated uptake of LDL was sensitive to treatment with phospholipase C and pronase and was dependent on the presence of Ca2+. PMB caused similar changes in human skin fibroblasts, bovine smooth muscle cells, and bovine endothelial cells, which suggests that PMB-enhanced LDL uptake is a general cellular phenomenon. Our results thus indicate that PMB increases cellular catabolism of LDL through an endocytotic pathway not involving the LDL receptors.
Liao
W
W
Department of Internal Medicine, Lund University, Malmö General Hospital, Sweden.
Florén
C H
CH
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular; D002417:Cattle; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D011112:Polymyxin B / Q000494:pharmacology*; D011402:Pronase / Q000494:pharmacology; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000502:physiology; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000494:pharmacology
D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002738:Chloroquine; D010738:Type C Phospholipases; D011402:Pronase; D011112:Polymyxin B; D003078:Colchicine; D002118:Calcium