Mouse CD36 Has Opposite Effects on LDL and Oxidized LDL Metabolism In Vivo

Abstract

Objective-The cluster of differentiation-36 (CD36) is a multifunctional protein which is recognized for its in vitro ability to take up oxidized low-density lipoproteins (oxLDL) in macrophages and is therefore considered atherogenic. It also binds LDL. Our objective was to define the physiological role of CD36 in both native LDL and oxLDL metabolism in mice. Methods and Results-Clearance studies of labeled LDL and oxLDL were conducted in wild-type, CD36 knockout (KO), scavenger receptor class B, type I (SR-BI) KO, and SR-BI/CD36 double KO mice. We found that CD36 impedes the disappearance of native LDL and favors that of oxLDL. This was confirmed by association and degradation assays with primary cultures of hepatic cells from wild-type and CD36 KO mice. In addition, our in vivo work indicates that neither SR-BI nor CD36 plays a significant role in cholesteryl esters (CE) selective uptake (SU) from oxLDL, whereas CD36, in absence of SR-BI, can selectively take CE from LDL. Conclusion-Our investigation showed for the first time that CD36 plays a significant role in oxLDL uptake in vivo in the mouse. As CD36 also retards LDL clearance, its atherogenic character may also relate to its negative effect on LDL catabolism. t is well established that high levels of plasma cholesterol associated with LDL increase the risk of developing atherosclerosis. The level of LDL in blood circulation is related to the synthesis rate of their precursors and their uptake by the liver. 1 A large part occurs through LDLreceptors (LDLr) which take up the entire LDL particles and lead to their complete degradation, a mechanism referred to as the holoparticle pathway. LDL can also selectively transfer their CE without concomitant degradation of their apolipoproteins, a process termed selective uptake (SU).SR-BI is a cell surface receptor recognized for its ability to selectively take up CE from high-density lipoproteins (HDL) 2 and LDL. 3 Our in vivo studies 4 showed that ablation of SR-BI expression in mice leads to the complete loss of LDL-CE SU early after injection. However, after an hour, an acceleration of CE disappearance was obvious in SR-BI KO mice, indicating that a SR-BI-independent pathway can rescue SR-BI deficiency. A potential candidate for the SR-BIindependent pathway is CD36, another class B scavenger receptor. This is supported by studies showing that COS cells overexpressing either SR-BI or CD36 are equipotent toward LDL-CE uptake. 5 However the physiological importance of CD36 in LDL-CE SU remains to be established in vivo. See accompanying article on page 1209LDL can undergo oxidative modification, and these are detectable in circulation. Many studies have used standard conditions generating fully oxidized LDL (oxLDL), which we refer simply as to oxLDL. Although oxLDL cannot interact with LDLr, it is known that injected oxLDL disappear faster than native LDL in rodents and that this uptake involves the liver. 6 In vivo studies by Ling et al 7 showed that the scavenger receptor class A type I/II (SR-A) is not impli...

Scavenger receptor CD36 mediates uptake of high density lipoproteins in mice and by cultured cells

“…This consistent change in HDL steadystate level is in agreement with a physiologic function of CD36 in HDL metabolism in vivo. Plasma triacylglycerol and fatty acids were not different between CD36 KO and WT animals in this study; this observation is in contrast to a previous report ( 15 ) but in agreement with another study ( 11 ). However, mouse strain-related genetic differences and specifi c experimental conditions (like diet) presumably explain the discrepancy.…”

“…This molecule is expressed in skeletal and heart muscle, liver, lungs, adipose tissue, spleen, small intestine, testis, capillary endothelium, microglia, and elicited peritoneal macrophages ( 10,11 ). The ligands of CD36 include native and oxidized lipoproteins, anionic phospholipids, thrombospondin, collagen, amyloid b , and plasmodium falciparum-infected erythrocytes ( 4,5,11,12 ). With respect to metabolism, CD36 facilitates the transfer of fatty acids into myocytes ( 10 ).…”

“…With respect to metabolism, CD36 facilitates the transfer of fatty acids into myocytes ( 10 ). Recently a role of CD36 for selective CE uptake from low density lipoprotein was proposed ( 11 ). On the basis of this broad ligand specifi city and its widespread expression, diverse functions of CD36 have been suggested, including atherogenesis and lipoprotein metabolism ( 4 ).…”

“…After 5 min, blood was obtained by retro-orbital bleeding, and plasma was frozen at 2 80°C. Pre-and postheparin plasma lipase activity were assayed using an artifi cial glycerol tri- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]oleatecontaining emulsion ( 33 ).…”

Developmental Endothelial Locus-1 (Del-1) Inhibits Oxidized Low-Density Lipoprotein Activity by Direct Binding, and Its Overexpression Attenuates Atherogenesis in Mice

“…38-40 Although Luangrath et al showed that CD36 partly mediates oxLDL clearance in vivo, when large amounts of oxLDL are applyed, the residual clearance mechanism(s) are still unknown. 39 In contrast, plasma LAB was decreased when Del-1 was overexpressed. This could occur even if oxLDL concentrations were the same, because LAB measures LOX-1-binding activity, which is blocked by Del-1.…”