Lysosomal density endocytosis

Dehydrogenase Deficiency, Biotinidase Deficiency, and Adrenoleukodystrophy. Catabolism of essential amino acid skeletons is discussed in the chapters Phenylketonuria and HMG-CoA Lyase Deficiency. The chapters Inborn Errors of Urea Synthesis and Neonatal Hyperbilirubinemia discuss the detoxification and excretion of amino acid nitrogen and of heme. The chapter Gaucher Disease provides an illustration of the range of catabolic problems that result in lysosomal storage diseases. Several additional chapters deal with key aspects of intracellular transport of enzymes and metabolic intermediates the targeting of enzymes to lysosomes (I-Cell Disease), receptor-mediated endocytosis (Low-Density Lipoprotein Receptors and Familial Hypercholesterolemia) and the role of ABC transporters in export of cholesterol from the cell (Tangier disease). 

Figure 12.40. Receptor-Mediated Endocytosis. The process of receptor-mediated endocytosis is illustrated for the cholesterol-carrying complex, low-density lipoprotein (LDL) (1) LDL binds to a specific receptor, the LDL receptor (2) this complex invaginates to form an internal vesicle (3) after separation from its receptor, the LDL-containing vesicle fuses with a lysosome, leading to degradation of the LDL and release of the cholesterol.

LPL converts chylomicrons to chylomicron remnants and VLDL to intermediate density lipoprotein (IDL). These products, which have a relatively low triacylglyc-erol content, are taken up by the liver by the process of endocytosis and degraded by lysosomal action. IDL may also be converted to low density lipoprotein (LDL) by further digestion of triacylglycerol. Endocytosis of LDL occurs in peripheral tissues as well as the liver (Table VI. 1), and is the major means of cholesterol transport and delivery to peripheral tissues. 

Cholesterol is packaged in chylomicrons in the intestine and in very-low-den-sity lipoprotein (VLDL) in the liver. It is transported in the blood in these lipoprotein particles, which also transport triacylglycerols. the triacylglycerols of the blood lipoproteins are digested by lipoprotein lipase, chylomicrons are converted to chylomicron remnants, and VTDT is converted to intermediate-density lipoprotein (IDL) and subsequently to low-density lipoprotein (LDL). These products return to the liver, where they bind to receptors in cell membranes and are taken up by endocytosis and digested by lysosomal enzymes. LDL is also endocy-tosed by nonhepatic (peripheral) tissues. Cholesterol and other products of lysosomal digestion are released into the cellular pools. The liver uses this recycled cholesterol, and the cholesterol that is synthesized from acetyl CoA, to produce VLDL and to synthesize bile salts. 

Pearse and Bretscher (1981) have discussed the role of coated vesicles in membrane synthesis and function. Eukaryotic cells are able to specifically take up macromolecules by absorptive endocytosis. The macromolecules are usually transferred to lyso-somes where they may be degraded. The first stage of the process involves the binding of macromolecules to receptors which are localized in coated pits. The latter are indented sites on the plasma membrane and the coated pit buds into the cytoplasm to form a coated vesicle in which lie the endocytosed macromolecules. The coated vesicle sheds its coat rapidly and the endocytic vesicles fuse with each other. This allows receptors to be returned to the plasma membrane while the contents are transferred to the lyso-somes. In order to explain how lysosomal and plasma membranes remain different, it was suggested that the coated pits are able to accept certain macromolecules while excluding others. The accepted proteins enter the coated pit and were presumed to bind directly or indirectly to clathrin. Clathrin, a 180000-dalton protein on the cytoplasmic face of coated pits, provides the polyhedron skeleton for the coated vesicles. Examples of the use of coated vesicles for mediated endocytosis are in the uptake of low-density lipoprotein from the blood and in humans for the transport of immunoglobulins from the mother to the child. For other mammals such as the rat the antibodies are selectively absorbed from the mother s milk by the intestinal epithelium. Coated vesicles also provide a mechanism for virus transport into cells. 

Fig. 2.6. Receptor-mediated endocytosis example of low density lipoprotein receptor with the following steps receptor-mediated pit formation, formation of vesicles, pH drop inside the vesicle, fusion with a sorting vesicle, recycling of a receptor, fusion with lysosome and digestion.

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