Uptake and processing of remnants of chylomicrons and very low density lipoproteins by rat liver

In the rat, chylomicron remnants and very low density lipoprotein (VLDL) remnants are taken up into the liver by high affinity processes and appear to undergo degra- dation by lysosomes. The relationship of this catabolic process to the known pathways of uptake and degradation of low density lipoproteins (LDL) and the involvement of nonparen- chymal cells are addressed in these studies. We have utilized both light and electron microscopic radioautography to deter- mine whether the pathway of intracellular transport and catab- olism resembles that established for LDL in hepatocytes. Ra- dioiodinated plasma VLDL remnants and lymph chylomicron remnants were injected into femoral veins of rats and the livers were fixed by perfusion 3 to 30 minutes later. Quantitative light microscopic radioautography showed little or no accu- mulation of grains over Kupffer cells. Electromicroscopic ra- dioautography confirmed these observations and, in addition, demonstrated that very few grains were associated with endo- thelial cells. The processing of the remnant particles closely resembled that of LDL. Following an initial association of grains with the parenchymal cell plasma membrane, frequently in regions in close proximity to clathrin-coated endocytic pits, the grains were found in endocytic vesicles just beneath the plasma membrane. By 15 minutes the grains were found over multivesicular bodies located in the Golgi-lysosome region of the cell. Thirty minutes after injection, radioautographic grains began to be associated with secondary 1ysosomes.l These data indicate no significant role for nonparenchymal cells in the internalization and subsequent degradation of triglyceride-rich lipoproteins, and provide evidence that the processing of remnants as well as LDL follows the classical pathway of receptor-mediated endocytosis.-Jones, A. L., G. T. Hradek, C. Hornick, G. Renaud, E. E. T. Windler, and R. J. Havel. Uptake and processing of remnants of chylomicrons and very low density lipoproteins by rat liver. J. Lipid Res. 1984. 25: 1151-1158. Supplementary key works hepatocytes electron microscopic ra- dioautography lysosomes multivesicular bodies coated pits vesicles 9 receptor-mediated endocytosis models suggests that, following the interaction of these triglyceride-rich lipoproteins with lipoprotein lipase within extrahepatic blood capillaries (6), the resulting remnants are rapidly bound to high affinity receptors on liver cells (7). In the rat, low density lipoproteins (LDL) are bound to specific receptors on hepatic paren- chymal cells, internalized by a well-defined pathway and catabolized in lysosomes (8- 10). Chylomicron remnants (1 1) and VLDL remnants (4, 12) are also thought to be processed by lysosomal pathways, but the relationship of these pathways to that described for LDL has not been defined in detail, and the role of nonparenchymal (Kupffer and endothelial) cells in remnant uptake and processing is controversial (4, 1 1, 13- 16). In the current studies, we have used methods of light and electron microscopic radioautography applied previously to the study of the LDL pathway in rat liver (10) to address these questions.