Lipoprotein receptor-mediated endocytosis

The bulk of pinocytosis in the nervous system is mediated by clathrin-mediated endocytosis (CME) [55] and this is the best-characterized pathway. More detail about clathrin-mediated pathways will be given when receptor-mediated endocytosis and the synaptic vesicle cycle pathways are considered. Pinocytosis through CME is responsible for uptake of essential nutrients such as cholesterol bound to low density lipoprotein (LDL) and transferring, but also plays a role in regulating the levels of membrane pumps and channels in neurons. Finally, CME is critical for normal synaptic vesicle recycling. 

VLDLs, IDLs, and LDLs are closely related to one another. VLDLs formed in the liver (see p. 312) transport triacylglycerols, cholesterol, and phospholipids to other tissues. Like chylomicrons, they are gradually converted into IDL and LDL under the influence of lipoprotein lipase [1]. This process is also stimulated by HDL. Cells that have a demand for cholesterol bind LDL through an interaction between their LDL receptor and ApoB-100, and then take up the complete particle through receptor-mediated endocytosis. This type of transport is mediated by depressions in the membrane ( coated pits"), the interior of which is lined with the protein clathrin. After LDL binding, clathrin promotes invagination of the pits and pinching off of vesicles ( coated vesicles"). The clathrin then dissociates off and is reused. After fusion of the vesicle with ly-sosomes, the LDL particles are broken down (see p. 234), and cholesterol and other lipids are used by the cells. 

Triglycerides are removed in extrahepatic tissues through a pathway shared with VLDL that involves hydrolysis by the lipoprotein lipase (LPL) system. Decrease in particle diameter occurs as triglycerides are depleted. Surface lipids and small apoproteins are transferred to HDL. The resultant chylomicron remnants are taken up by receptor-mediated endocytosis into hepatocytes. 

The LDL receptor also binds to apoE and plays a significant role in the hepatic uptake of chylomicrons and VLDL remnants. However, if LDL receptors are unavailable (as, for example, in a mouse strain that lacks the gene for the LDL receptor), VLDL remnants and chylomicrons are still taken up by the liver even though LDL is not. This indicates the presence of a back-up system for receptor-mediated endocytosis of VLDL remnants and chylomicrons. One back-up receptor is lipoprotein receptor-related protein (LRP), which binds to apoE as well as to a number of other ligands. 

Production of LDL from VLDL in the plasma With these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle, the intermediate-density lipoprotein (IDL) or VLDL remnant, is observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand. [Note Apolipoprotein E is normally present in three isoforms, E2, E3, and E4. Apo E2 binds poorly to receptors, and patients who are homozygotic for apo E2 are deficient in the clearance of chylomicron remants and IDLs. The individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia, or broad beta disease), with hypercholesterolemia and premature atherosclerosis. Not yet understood is the fact that the E4 isoform confers increased susceptibility to late-onset Alzheimer disease.]... 

HDL is a reservoir of apolipoproteins HDL particles serve as a circulating reservoir of apo C-ll (the apolipoprotein that is transferred to VLDL and chylomicrons, and is an activator of lipoprotein lipase), and apo E (the apolipoprotein required for the receptor-mediated endocytosis of IDLs and chylomicron remnants). 

Goldstein, J.L., R.G. Anderson, and M.S. Brown. 1982. Receptor-mediated endocytosis and the cellular uptake of low density lipoprotein. Ciba Found Symp 11. 

Chylomicrons are synthesized in the intestine and transport dietary triacylglycerols to skeletal muscle and adipose tissue, and dietary cholesterol to the liver. At these target tissues the triacylglycerols are hydrolyzed by lipoprotein lipase on the surface of the cells and the released fatty acids are taken up either for metabolism to generate energy or for storage. The resulting cholesterol-rich chylomicron remnants are transported in the blood to the liver where they are taken up by receptor-mediated endocytosis. 

VLDLs are synthesized in the liver and transport triacylglycerols, cholesterol and phospholipids to other tissues, where lipoprotein lipase hydrolyzes the triacylglycerols and releases the fatty acids for uptake. The VLDL remnants are transformed first to IDLs and then to LDLs as all of their apoproteins other than apoB-100 are removed and their cholesterol esterified. The LDLs bind to the LDL receptor protein on the surface of target cells and are internalized by receptor-mediated endocytosis. The cholesterol, which is released from the lipoproteins by the action of lysosomal lipases, is either incorporated into the cell membrane or re-esterified for storage. High levels of intracellular cholesterol decrease the synthesis of the LDL receptor, reducing the rate of uptake of cholesterol, and inhibit HMG CoA reductase, preventing the cellular synthesis of cholesterol. 

HDLs have the opposite function to that of LDLs in that they remove cholesterol from the tissues. The HDLs are synthesized in the blood mainly from components derived from the degradation of other lipoproteins. HDLs then acquire their cholesterol by extracting it from cell membranes and converting it into cholesterol esters by the action of LCAT (Fig. 1). The HDLs are then either taken up directly by the liver or transfer their cholesterol esters to VLDLs, of which about half are taken up by the liver by receptor-mediated endocytosis (Fig. 1). The liver is the only organ that can dispose of significant quantities of cholesterol, primarily in the form of bile salts (see Topic K5). 

Brown, M.S., and J.L. Goldstein. Receptor-mediated endocytosis Insights from the lipoprotein receptor system. Proc. Natl. Acad. Sci. U.S.A. 76 3330-3337,... 

Abbreviations and trivial names used are RME, receptor-mediated endocytosis LDL, low density lipoprotein EGF. epidermal growth factor SDS, sodium dodecyl sulfate LH, luteinizing hormone hCG, human chorionic gonadotropin and G protein, guanine nucleotide binding protein. 

In hepatocytes, vitamin E can take two routes. A fraction of it is packaged as VLDL and reenters the circulation, while excess is excreted in the bile. Plasma lipolysis of the VLDL particle again results in release not only of lipids, but also of vitamin E, with the remainder left with the LDL particles. This fraction can be further distributed to tissues via LDL receptor-mediated endocytosis or transferred between lipoproteins, mainly to HDL, by plasma lipid transfer proteins. Thus, mobilization of vitamin E from intestinal and liver... 

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 5.6 General scheme of lipoprotein metabolism. Triacylglycerols and cholesterol are exported from the liver in VLDLs, containing apolipoprotein B-lOO they further acquire apo-C-I, II, III and apo-E from circulating HDL. Apo-C-II activates lipoprotein lipase to remove fatty acids from VLDLs. As triacylglycerols are removed, VLDLs transform to IDEs and finally LDLs. LDLs are the main vehicle for transfer of cholesterol to the tissues uptake of LDL occurs primarily in the liver through LDL-receptor-mediated endocytosis, which requires the presence of apo-B-100. HDLs are synthesised essentially devoid of cholesterol or triacylglycerol and provide a circulating source of apo-C-I, II and apo-E. HDLs gradually accumulate cholesteryl esters, eventually returning these to the liver, mediated by an apo-A-I receptor this is referred to as reverse cholesterol transport. ...

Chylomicrons are produced from dietary fat by the removal of resynthesised triglycerides from the mucosal cells of the small intestine into the intestinal lumen. These then enter the circulation via the thoracic dncts in the lymphatic system and enter into the subclavian veins, where triglyceride content is reduced by the action of lipoprotein lipases (LPL) on capillary endothelial surfaces in skeletal muscle and fat. The free fatty acids (FFA) from the triglycerides are used by the tissues as an energy source or stored as triglycerides. The chylomicron remnants, stripped of triglyceride and therefore denser, are then taken up by the liver by LDL receptor-mediated endocytosis, thereby delivering cholesterol to the liver. 

Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis. ApoE, the major apolipoprotein of the chylomicron in the brain, binds to a specific receptor and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants (Mahley et al., 1999). In the brain, lipidated apoE binds aggregated in a isoform-speciflc manner, apoE4 being much more effective than the other forms,... 

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.

B-48, E Receptor-mediated endocytosis by liver B-lOO, C, E Hydrolysis by lipoprotein lipase... 

Receptor-mediated endocytosis plays a key role in cholesterol metabolism (p. 745). Some cholesterol in the blood is in the form of a lipid—protein complex called low-density lipoprotein (LDL). Low-density lipoprotein... 

LDL Low-density lipoprotein a product of the degradation of very-low-density lipoproteins (VLDLs) by the action of lipoprotein lipase. LDLs are taken up by a receptor-mediated endocytosis by both peripheral tissues and the liver. It is commonly called the bad cholesterol. ... 

Cholesterol, which is largely insoluble in aqueous m a, travels through the blood circulation in the form of Upoprotein complexes. The plasma lipoproteins are a family of globular particles that share common structural features. A core of hydrophobic lipid, principally triacylglycerols (triglycerides) and cholesterol esters, is surrounded by a hydrophilic monolayer of phospholipid and protein (the apolipoproteins) [1-3]. Lipid-apolipoprotein interactions, facihtated byi amphi-pathic protein helices that segregate polar from nonpolar surfaces [2,3], provide the mechanism by which cholesterol can circulate in a soluble form. In addition, the apolipoproteins modulate the activities of certain enzymes involved in Upoprotein metabolism and interact with specific cell surface receptors which take up Upopro-teins by receptor-mediated endocytosis. Differences in the Upid and apoUpoprotein compositions of plasma Upoproteins determine their target sites and classification based on buoyant density. 

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