Hepatocytic lipoprotein receptors and intracellular lipoprotein catabolism

Abstract

Hepatocytes, as the major site of synthesis and terminal catabolism of plasma lipoproteins, exert the major regulatory influence on the concentration of atherogenic lipoproteins in blood plasma and may thereby influence the rate of atherogenesis. The LDL receptor on the microvillous sinusoidal surface of hepatocytes mediates the catabolism of remnants of triglyceride-rich lipoproteins and LDL. Binding of VLDL remnants to the receptor, mediated by apo E, is of very high affinity and presumably multivalent, whereas binding of LDL, mediated by apo B-100, is monovalent and of lower affinity, accounting for the much longer residence time of the latter in the blood. The magnitude of the influx of lipoprotein particles into hepatocytic endosomal compartments dwarfs that of other macromolecules undergoing receptor-mediated endocytosis and terminal catabolism in lysosomes of these cells. The intracellular compartments and processing steps in hepatocytic lipoprotein uptake and degradation are essentially the same as those described for other ligands in the liver and other cells. Receptors with bound lipoproteins migrate into coated pits which become coated vesicles. These vesicles uncoat and fuse to form CURL vesicles and tubules near the cell surface where most receptors are recycled, presumably via receptor-rich appendages that become separated from the vesicles. CURL vesicles become mature MVBs as they migrate to the Golgi/bile canalicular pole of hepatocytes, where they fuse with putative Golgi-derived primary lysosomes and are transformed into heterophagic secondary lysosomes. MVBs also contain a receptor-rich appendage that may recycle some receptors directly to the cell surface or through adjacent Golgi compartments. Dilated ends of trans-Golgi cisternae contain nascent VLDL undergoing packaging for secretion following their synthesis and assembly in the endoplasmic reticulum. Because these "forming secretory vesicles" resemble remnant-filled MVBs, occur in a similar location in the Golgi area of hepatocytes and coisolate in centrifugal fractions of liver homogenates, there has been considerable confusion about the identity of these compartments. With the aid of specific endocytic and exocytic markers, highly purified and morphologically intact endosomal and Golgi compartments can now be obtained from rat liver homogenates. The availability of these and similar fractions of defined purity should facilitate investigation of the hepatocytic processing of endocytosed and secreted macromolecules. Although chylomicron remnants are also taken up by receptor-mediated endocytosis, the nature of the hepatocytic remnant receptor remains elusive.(ABSTRACT TRUNCATED AT 400 WORDS)

ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2

“…Alternatively, the process of LDLR internalization may differ in hepatocytes and fibroblasts. For example, most LDLRs are clustered in coated pits in fibroblasts but appear to be dispersed on the plasma membrane in hepatocytes (31,32). ARH may perform a specific function in hepatocytes that is not required in fibroblasts.…”

Dissection of the multifunctional “receptor-recycling” endocytic compartment of hepatocytes

“…30,31 This subcellular fractionation procedure distinguishes 3 endosomal fractions on the basis of their morphology and their association with, or the absence of, various radioligands at different time points: ''early'' (compartment of uncoupling receptors and ligands [CURL]) and ''late'' (multivesicular bodies [MVB]) endosomes and a third endosomal fraction, the receptor-recycling compartment (RRC), which is enriched in recycling receptors and depleted of ligands. 27,32 Although biochemical analyses have shown a very similar protein composition, 28 the electron microscopy study of the isolated endosomes showed ultrastructural differences between the fractions 27,29,31,33 (Fig. 1).…”

Effect of Specific Binding of High Density Lipoprotein to Eel Hepatocytes on Their Secretion of Lipoprotein.

“…This seemed to be due to the VLDL-(or chylomicron-) like lipoprotein triggering an efflux of intracellular lipids. In mammalian cultured cells such as small intestinal crypt cells (3,4) and fibroblasts (5), HDL is resecreted with intracellular cholesterol following endocytosis after binding of HDLto the cells (3,4,8,26,27,29), or HDL withintracellular cholesterol is released from the specific binding proteins of plasma membraneof the cells following cellular signal induction such as the activation of phospholipase D and protein kinase C (4-7, 24). In these cells HDLis the only lipoprotein to participate in the efflux of cholesterol.…”

“…These characteristics of the effects of HDLdescribed above suggest the novel role of HDLin the transport of lipids. Though there are two hypotheses on the role of HDLfor cholesterol efflux, namely HDL-retroendocytosis (3,4,8,26,27,29) and cellular signal transducing by HDL(4-7, 24), neither hypotheses seems to be applicable to the role of eel serum HDL,since HDLin eel hepatocytes seems only to provide the initial step for the transport of lipids and HDLitself seems not to participate in transporting intracellular lipids. Instead, a VLDL-(or chylomicron-) like lipoprotein transports the intracellular lipids in eel hepatocytes.…”