Processing of acetylated human low-density lipoprotein by parenchymal and non-parenchymal liver cells. Involvement of calmodulin?
1. Modified lipoproteins have been implicated to play a significant role in the pathogenesis of atherosclerosis. In view of this we studied the fate and mechanism of uptake in vivo of acetylated human low-density lipoprotein (acetyl-LDL). Injected intravenously into rats, acetyl-LDL is rapidly cleared from the blood. At 10min after intravenous injection, 83% of the injected dose is recovered in liver. Separation of the liver into a parenchymal and non-parenchymal cell fraction indicates that the non-parenchymal cells contain a 30-50-fold higher amount of radioactivity per mg of cell protein than the parenchymal cells. 2. When incubated in vitro, freshly isolated non-parenchymal cells show a cell-association of acetyl-LDL that is 13-fold higher per mg of cell protein than with parenchymal cells, and the degradation of acetyl-LDL is 50-fold higher. The degradation of acetyl-LDL by both cell types is blocked by chloroquine (10-50mum) and NH(4)Cl (10mm), indicating that it occurs in the lysosomes. Competition experiments indicate the presence of a specific acetyl-LDL receptor and degradation pathway, which is different from that for native LDL. 3. Degradation of acetyl-LDL by non-parenchymal cells is completely blocked by trifluoperazine, penfluridol and chlorpromazine with a relative effectivity that corresponds to their effectivity as calmodulin inhibitors. The high-affinity degradation of human LDL is also blocked by trifluoperazine (100mum). The inhibition of the processing of acetyl-LDL occurs at a site after the binding-internalization process and before intralysosomal degradation. It is suggested that calmodulin, or a target with a similar sensitivity to calmodulin inhibitors, is involved in the transport of the endocytosed acetyl-LDL to or into the lysosomes. 4. It is concluded that the liver, and in particular non-parenchymal liver cells, are in vivo the major site for acetyl-LDL uptake. This efficient uptake and degradation mechanism for acetyl-LDL in the liver might form in vivo the major protection system against the potential pathogenic action of modified lipoproteins.
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D014018:Tissue Distribution; D014268:Trifluoperazine / Q000494:pharmacology
D014150:Antipsychotic Agents; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D008077:Lipoproteins, LDL; C032629:acetyl-LDL; D000643:Ammonium Chloride; D014268:Trifluoperazine; D002738:Chloroquine; D002118:Calcium