Low density lipoprotein receptors pathways

Brown and Goldstein described the low-density lipoprotein receptor pathway. 

S. Vitols, G. Gahrton and C. Peterson, Significance of the low-density lipoprotein receptor pathway for the in vitro accumulation of AD-32 incorporated into LDL in normal and leukemic white blood cells, Cancer Treat. Rep. 68 (1984) 515-520. 

S.G. Vitols, M. Masquelier and C.O. Peterson, Selective uptake of a toxic lipophilic anthracycline derivative by the low-density lipoprotein receptor pathway in cultured fibroblasts, J. Med. Chem. 28 (1985) 451-454. 

The rationale for this type of contrast agent is to use the endogenous metabolic pathway of lipid metabolism in the liver for the transport of iodinated substances. Chylomicron remnants are naturally occurring lipoproteins in the blood that are responsible for the transport of lipids into the liver. Three different mechanisms for this transport are discussed direct uptake by the low-density lipoprotein receptor transport to the low-density lipoprotein receptor-related protein (LRP) mediated by heparan sulfate proteoglycan (HSPG) or direct HSPG-LRP uptake and direct HSPG uptake. One of the prerequisites for particles to be transported by these mechanisms is a mean diameter of less than 100-300 run. 

Whereas ICAM-1 clearly mediates attachment and infection of the major group of HRVs, the human low-density lipoprotein receptor (LDLR) has been identified as the receptor for the minor group of rhinoviruses, including HRV2 (Hofer et al, 1994). The LDLR appears to mediate internalization of HRV2 via a classic endocytic pathway. Subsequently, the transfer of viral RNA occurs from the endosome/late endosome through a pore in the endosomal membrane (Prchla et al, 1995). 

Fig. 30.5. Endogenous and exogenous pathways for lipid transport and metabolism. FFA, free fatty acids LDLR, low-density lipoprotein receptor FC, free unesterified cholesterol LCAT, lecithin-cholesterol acyltransferase.

Apolipoprotein E (apoE) is an important lipid transport protein in human plasma and brain. It mediates hepatic clearance of remnant lipoproteins as a high-affin-ity ligand for the low-density lipoprotein receptor (LDLR) family, including LDLR, LDLR-related protein (LRP), and cell surface heparan sulfate PGs (71). In the liver, heparan sulfate PGs facilitate the interaction of remnant particles with LRP, which is known as the heparan sulfate PG-LRP pathway, in which apoE initially interacts... 

The role of NFkB has been reviewed in ref. 205. NFkB is a key regulator of inflammation, immune responses, cell survival, and cell proliferation inhibition of the NFkB pathway in macrophages leads to more severe atherosclerosis in low density lipoprotein receptor (LDLR) deficient mice, possibly by affecting the pro- and anti-inflammatory balance that controls the development of atherosclerosis (reduced production of LPS-stimulated TNF, and reduction in IL-10) (206). 

FIGURE 3.2.2 Metabolic pathways of carotenoids such as p-carotene. CM = chylomicrons. VLDL = very low-density lipoproteins. LDL = low-density lipoproteins. HDL = high-density lipoproteins. BCO = p-carotene 15,15 -oxygenase. BCO2 = p-carotene 9, 10 -oxygenase. LPL = lipoprotein lipase. RBP = retinol binding protein. SR-BI = scavenger receptor class B, type I. 

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. 

Uptake of low-density lipoprotein has been studied479 as a prototype of a receptor-mediated pathway for internalization of external macromolecules. It is a coupled process by which selected, extracellular proteins or peptides are first bound to specific, cell-surface receptors, and then rapidly internalized by the cell. Internalization follows clustering of receptors in specialized regions of the cell surface, called coated pits, that invaginate, to form coated vesicles. 

Fig. 5.2.1 The major metabolic pathways of the lipoprotein metabolism are shown. Chylomicrons (Chylo) are secreted from the intestine and are metabolized by lipoprotein lipase (LPL) before the remnants are taken up by the liver. The liver secretes very-low-density lipoproteins (VLDL) to distribute lipids to the periphery. These VLDL are hydrolyzed by LPL and hepatic lipase (HL) to result in intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), respectively, which then is cleared from the blood by the LDL receptor (LDLR). The liver and the intestine secrete apolipoprotein AI, which forms pre-jS-high-density lipoproteins (pre-jl-HDL) in blood. These pre-/ -HDL accept phospholipids and cholesterol from hepatic and peripheral cells through the activity of the ATP binding cassette transporter Al. Subsequent cholesterol esterification by lecithinxholesterol acyltransferase (LCAT) and transfer of phospholipids by phospholipid transfer protein (PLTP) transform the nascent discoidal high-density lipoproteins (HDL disc) into a spherical particle and increase the size to HDL2. For the elimination of cholesterol from HDL, two possible pathways exist (1) direct hepatic uptake of lipids through scavenger receptor B1 (SR-BI) and HL, and (2) cholesteryl ester transfer protein (CfiTP)-mediated transfer of cholesterol-esters from HDL2 to chylomicrons, and VLDL and hepatic uptake of the lipids via the LDLR pathway...

Reactive pathway may follow the stimulation of angiotensin II receptors, which activate the NADPH oxidase (5). Hypertension may generate OS via this mechanism. Afurther reactive mechanism is related to the oxidized low-density lipoproteins (LDL) or even to the activity of free cholesterol on macrophages (6). 

Polypeptides are substrates for receptor-mediated transcytosis. Cerebral insulin reaches the brain from the circulation via receptor-mediated transcytosis through the BBB on the brain endothelial insulin receptor. This receptor is upregulated in development and downregulated in streptozotocin-induced diabetes mellitus. Similarly a BBB transferrin receptor mediates the transcytosis of transferrin across the BBB and this explains how the brain is able to extract iron from the circulation. Other RMT pathways consituting portals of entry to the brain for circulating peptides include receptors for insulin-like growth factors, cationic proteins, lectins, acetyl-low density lipoprotein and leptin. 

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