Scavenger receptor promoter

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.

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. 

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... 

Reaven E., Leers-Sucheta S., Nomoto A. and Azhar S. (2001) Expression of scavenger receptor class B type 1 (SR-BI) promotes microvillar channel formation and selective cholesteryl ester transport in a heterologous reconstituted system. Proc. Natl. Acad. Sci. USA 98, 1613-1618. 

Plasma LDL (bad cholesterol) promotes foam cell formation and thus atherosclerosis by a LDLR-independent mechanism apparendy requiring scavenger receptors (see Figure 18-20). 

Podrez, E.A. et al. A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions 1. J. Biol. Chem. 277 (2002a) 38517-23. 

Because of a rapid equilibrium between HDL core and surface lipids, CETP, phospholipid transfer protein, HL, EL, and scavenger receptor-BI each has the potential to modify the HDL surface lipid composition, and indirectly alter the affinity of apo A1 for HDL (Fig. 8). There is presently insufficient evidence to assess the relative significance of these factors in promoting apo A1 recycling or RCT either in human plasma or in mice. The most direct link between recycling and pre-beta,-HDL is that now linked to apo M in mice. 

The lured monocytes mature into macrophages. The macrophages along with T cells produce inflammatory mediators such as cytokines, which promote cell division. Scavenger receptors displayed on the macrophage help them digest modified LDLs. 

Fig. 1. Oxidation hypothesis. Proposes minimally modified LDL is formed due to oxidation in the arterial intimal space. This LDL can still be taken up by the LDL receptor, but minimally modified LDL promotes release of proinflammatory mediators from monocytes and acts as a monocyte inhibition factor (MIF), reducing the motility of monocytes and thus leading to recruitment of macrophages (J4, W9). Macrophages further oxidize LDL (OxLDL), release inflammatory mediators, and rapidly take up OxLDL and other lipoproteins via the unregulated scavenger receptor that binds modified apo B to form lipid-laden foam cells. OxLDL is cytotoxic to a variety of cells in culture and may disrupt endothelial tissue, causing the release of inflammatory mediators and the entry of more LDL into the intimal space. Continued accumulation of monocytes and their differentiation into macrophages leads to a vicious cycle (J4, W9). Adapted from reference J4.

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