Hepatocellular processing of endocytosed proteins

Abstract

In conclusion, proteins of hepatobiliary transport utilize receptor-mediated endocytosis and intracellular vesicles and rely on functionally dynamic microtubules for their transport by hepatocytes. The many diverse transport pathways in hepatocytes reflect the many functions served by the uptake of various proteins from the blood. The mechanisms of sorting of ligands and their receptors in endosomes and the factors that regulate the intracellular transport pathways are not yet known. Future investigations in this area promise to yield many exciting discoveries about the hepatocellular processing of proteins.

Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

“…Mechanisms of Protein Disposition Soluble material, such as lipid particles, im mune complexes, bacterial toxins, certain lyso somal enzymes as well as denatured or other wise abnormal glycoproteins, can be handled by the liver by a versatile apparatus for recep tor-mediated uptake and degradation [114], Endocytosis is not specific for the liver cells but occurs in all eukaryotic cells except mature red blood cells [2,67,97,115,116], At least three different endocytotic mech anisms can be involved in the interiorization of such materials [67,97], Acinar Heterogeneity in Uptake For a number of compounds such as ga lactose [70], parathion [27,28] and paraoxon [113], acinar gradients are observed in nor mal perfusions. Since no further data are available, this heterogeneous involvement cannot yet be ascribed to intrinsic differ (1) Fluid phase endocytosis or pinocytosis is a nonsaturable engulfment process that does not require membrane binding.…”

“…(2) Adsorptive endocytosis or pinocytosis operates through an aspecific binding of the substrate to the membrane by which the sub strate becomes concentrated and is endocytosed more efficiently than via a fluid phase mechanism [20], (3) Receptor-mediated endocytosis in volves binding to more specific receptors [2,[114][115][116][117][118], Among the macromolecules that undergo receptor-mediated endocytosis are growth factors, hormones, transport proteins, pro teins destined for degradation such as a2-macroglobulin, proteins to be transported across polarized cells (IgA) as well as toxins and viruses. After binding of the ligand to the receptor, coated pits are formed that are internalized as coated vesicles.…”

“…These vesi cles are uncoated, acidified and subse quently fuse with primary lysosomes, where the protein is degraded [115,119,120], A large number of receptor-mediated pro cesses have been identified on hepatocytes, endothelial cells and Kupffer cells. On hepato cytes one finds the asialoglycoprotein (ASGP) receptor, recognizing galactose and N-acetylgalactosamine-terminated glycoproteins [67,97,[115][116][117], a receptor for plgA (called se cretory component) [116], in addition to re ceptors for high-density lipoprotein particles [97], epidermal growth factor [116], transfer rin [119], hemopexin, chylomicron remnants, hemoglobin, insulin and peptide hormones [ 121 ], as well as for lysosomal proteases (after complex formation with a2-macroglobulins) [67,114], The Kupffer and endothelial cells also contain several sugar-recognizing recep tors, different from those present on the hepa tocytes [2,67,97,114,116,122].…”

“…Since various cell types may 'compete' for the same substrate, dose dependency should be taken into account in measuring the relative clearance of macromolecules by the various cell types, as well as cell-specific drug targeting with glycoproteins [12, 97,118] , Acinar Heterogeneity in Protein Disposition The distribution of the above-mentioned receptor systems on the cell surfaces along the sinusoids is not well known. Some ear lier reports provided evidence for a hetero geneous acinar binding of asialo-alkaline phosphatase, preferentially in zone 3 [36,37], epidermal growth factor [35] and asialoorosomucoid (ASOR) in zone 1 [12] in rat liver, whereas insulin, IgA and apolipoprotein B are homogeneously distributed upon injection [116]. The finding of McFarlane et al [125] that antibodies against the ASGP receptor predominantly bind in zone 1 is in contradiction with the results of van der Sluijs et al who further investi gated the acinar distribution of the ASGPprocessing system using 125I-ASOR in antegradely and retrogradely perfused rat livers, by performing quantitative autoradiography [12], A gradient was observed descending from zone-1 to zone-3 cells upon perfusion in the normal direction.…”

The immunobiology of bile and biliary epithelium

“…It has been reported that in humans, the epithelial cells of biliary ductules are involved in the synthesis of the secretory component and the transport of sIgA into the bile. 12 It is believed that IgA passes through the cells by first binding to the secretory component in the basolateral side of the cell. [13][14][15] Using isolated and cultured cells, Sakisaka 16 demonstrated that labeled pIgA2 was transported transcellularly via the tubulovesicular pathways and secreted into the bile canalicular space in cultured rat hepatocytes, while it was transported via the tubulovesicular pathway and secreted into the luminal spaces in cultured guinea pig BEC.…”