Lipoprotein scavenger receptors

Oxidative modification of LDL within the artery wall has been implicated in the early stages of atherosclerotic lesion formation through the formation of lipid hydroperoxides (LOOH) within the LDL particle (Steinberg etal., 1989). This event then initiates radical chain oxidation reactions of unsaturated LDL lipids, thus yielding more anionic modified lipoprotein species with increased affinity for lipoprotein scavenger receptors. 

Figure 25-5. Metabolism of high-density lipoprotein (HDL) in reverse cholesteroi transport. (LCAT, lecithinxholesterol acyltransferase C, cholesterol CE, cholesteryl ester PL, phospholipid A-l, apolipoprotein A-l SR-Bl, scavenger receptor B1 ABC-1, ATP binding cassette transporter 1.) Prep-HDL, HDLj, HDL3—see Table 25-1. Surplus surface constituents from the action of lipoprotein lipase on chylomicrons and VLDL are another source of preP-HDL. Hepatic lipase activity is increased by androgens and decreased by estrogens, which may account for higher concentrations of plasma HDLj in women.

Fig. 2.1 Sequence of events in atherogenesis and role of low-density lipoprotein. Native LDL, in the subendothelial space, undergoes progressive oxidation (mmLDL) and activates the expression of MCP-1 and M-CSF in the endothelium (EC). MCP-1 and M-CSF promote the entry and maturation of monocytes to macrophages, which further oxidise LDL (oxLDL). Ox-LDL is specifically recognised by the scavenger receptor of macrophages and, once internalised, formation of foam cells occurs. Both mmLDL and oxLDL induce endothelial dysfunction, associated with changes of the adhesiveness to leukoc)des or platelets and to wall permeability.

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. 

Graham, A., Hogg, N., Kalyanaraman, B., O Leary, V.J., Darley-Usmar, V. and Moncada, S. (1993). Peroxynitrite modification of low density lipoprotein leads to recognition by the macrophage scavenger receptor. FEBS Lett. 330, 181-185. 

Haberland, M.E., Olch, C.L. and Fogelman, A.M. (1984). Role of lysines in mediating interaction of modifed low density lipoproteins with the scavenger receptor of human monocyte macrophages. J. Biol. Chem. 259, 11305-11311. 

Steinbrecher, U.P., Lougheed, M., Kwan, W.-C. and Dirks, M. (1989). Recognition of oxidised low density lipoprotein by the scavenger receptor of macrophages results from the derivatisa-tion of apo lipoprotein B. J. Biol. Chem. 264, 15216-15233. 

Parthasarathy, S., Putz, D.J., Boyd, D., Joy, L. and Steinberg, D. (1986). Macrophage oxidation of low density lipoprotein generates a modified form recognised by the scavenger receptor. Arteriosclerosis 6, 505-510. 

Minami M, Kume N, Shimaoka T, et al. Expression of scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX) in human atheroma. Ann N Y Acad Sci 2001 947 373-376. 

Shimaoka T, Kume N, Minami M, et al. Molecular cloning of a novel scavenger receptor for oxidized low density lipoprotein, SR-PSOX, on macrophages. J Biol Chem 2000 275(52) 40663-40666. 

The roles of lipoprotein and scavenger receptors, particularly SR-BI/II and CD36, in carotenoid uptake in the RPE cells still awaits exhaustive investigation. 

While it may be speculated that in the RPE both lipoprotein and/or scavenger receptors are likely to be involved in carotenoid uptake from the blood, it is not clear what mechanism(s) are responsible for carotenoid transport through the RPE into the neural retina. Also, it is not clear what mechanism(s) are responsible for selective accumulation in the retina of only two carotenoids. 

Acton, S, Rigotti, A, Landschulz, KT, Xu, S, Hobbs, HH, and Krieger, M, 1996. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271, 518-520. 

Ji, Y, Jian, B, Wang, N, Sun, Y, Moya, ML, Phillips, MC, Rothblat, GH, Swaney, JB, and Tall, AR, 1997. Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux. J Biol Chem 272, 20982-20985. 

Lorenzi, I, von Eckardstein, A, Cavelier, C, Radosavljevic, S, and Rohrer, L, 2008. Apolipoprotein A-I but not high-density lipoproteins are internalised by RAW macrophages Roles of ATP-binding cassette transporter A1 and scavenger receptor BI. JMolMed 86, 171-183. 

Tserentsoodol, N, Gordiyenko, NV, Pascual, I, Lee, JW, Fliesler, SJ, and Rodriguez, IR, 2006a. Intraretinal lipid transport is dependent on high density lipoprotein-like particles and class B scavenger receptors. 

Webb, NR, Connell, PM, Graf, GA, Smart, EJ, de Villiers, WJ, de Beer, FC, and van der Westhuyzen, DR, 1998. SR-BII, an isoform of the scavenger receptor BI containing an alternate cytoplasmic tail, mediates lipid transfer between high density lipoprotein and cells. J Biol Chem 273, 15241-15248. 

Since Lp(a) binds to fibrin, it can be directed to sites of fibrin deposition (vascular injury), providing a high concentration of cholesterol-rich lipoprotein that then can be taken up by macrophages via their scavenger receptors. This... 

X.-A. Li, W. B. Titlow, B. A. Jackson, N. Giltiay, M. Nikolova-Karakashian, A. Uittenbogaard, and E. J. Smart. High Density Lipoprotein Binding to Scavenger Receptor, Class B, Type I Activates Endothelial Nitric-oxide Synthase in a Ceramide-dependent Manner. J. Biol. Chem. 277 11058-11063 (2002). 

Mohamed, A. I., A. S. Hussein, S. J. Bhathena, and Y. S. Hafez. The effect of dietary menhaden, olive, and coconut oil fed with three levels of vitamin E on plasma and liver lipids and plasma fatty acid composition in rats. J Nutr Biochem 2002 13(7) 435-441. Kawano, K., S. Qin S, C. Vieu, X. Collet, and X. C. Jiang. Role of hepatic lipase and scavenger receptor BI in clearing phospholipid/free cholesterol-rich lipoproteins in PLTP-deficient... 

Cellular components in atherosclerotic plaques include foam cells, which are transformed macrophages, and smooth muscle cells filled with cholesteryl esters. These cellular alterations result from endocytosis of modified lipoproteins via at least four species of scavenger receptors. Chemical modification of lipoproteins by free radicals creates ligands for... 

The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not cause endocytosis of the lipoproteins. 

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...

The HDL lipids are removed from the circulation by a selective uptake and by an indirect pathway. The selective uptake of cholesterol esters from HDL into he-patocytes and steroidogenic cells is mediated by the binding of HDL to scavenger receptor B1 (SR-BI). This selective uptake by SR-BI may depend on the presence of cofactors such as HL, which hydrolyses phospholipids on the surface of both HDL and plasma membranes and thereby enables the flux of cholesteryl esters from the lipoprotein core into the plasma membrane [42]. The indirect pathway involves the enzyme CETP, which exchanges cholesteryl esters of a-HDL with triglycerides of chylomicrons, VLDL, IDL, and LDL. The a-HDL derived cholesteryl esters are therefore removed via the LDL-receptor pathway. The removal of excess cholesterol from the periphery and the delivery to the liver for excretion in the bile is termed reverse cholesterol transport. 

As mentioned in Chapter 21, there are several related receptors with similar structures. Two of them have a specificity for apolipoprotein E and can accept remnants of VLDL particles and chylomicrons.216 220 The LDL receptor-related protein is a longer-chain receptor.216 221 LDL particles, especially when present in excess or when they contain oxidized lipoproteins, may be taken up by endocytosis into macrophages with the aid of the quite different scavenger receptors.221 225 The uptake of oxidized lipoproteins by these receptors may be a major factor in promoting development of atherosclerosis (Box 22-B). On the other hand, scavenger receptor SR-B1, which is also present in liver cells, was recently identified as the receptor for HDL and essential to the "reverse cholesterol transport" that removes excess cholesterol for excretion in the bile.213/213a... 

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