Lipoproteins transport many vitamins and hormones that have been shown to be necessary for bone formation. However, the metabolism of LDL and HDL 3 by bone-forming osteoblastic cells remains unknown. Here we report that osteoblastic cells express scavenger receptors of class B that are implicated in the uptake of cholesterol and estradiol from LDL and HDL 3 . Introduction:The bone tissue is continuously remodeled, and its integrity requires a balance between osteoclastic bone resorption and osteoblastic bone formation. Recent studies have reported the importance of triglyceride-rich lipoproteins for the delivery of lipophilic vitamins necessary for normal bone metabolism. However, the ability of osteoblastic cells to process low-and high-density lipoproteins (LDL and HDL 3 ) and the receptors involved remain unknown. Materials and Methods: Binding, competition, degradation, and selective uptake assays with LDL and HDL 3 radiolabeled in their protein and lipid moieties or with [

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...

The physiological role of murine scavenger receptor class B type I (SR-BI) was evaluated by in vivo clearances of human HDL 3 and LDL in normal and SR-BI knockout (KO) mice. In normal mice, cholesteryl esters (CEs) were removed faster than proteins, indicating a selective uptake process from both HDL 3 and LDL. SR-BI KO mice showed 80% losses of HDL-CE selective uptake and the complete loss of LDL-CE selective uptake in the first phase of clearance. However, the second phase was characterized by an acceleration of CE disappearance in SR-BI KO mice. Thus, SR-BI is the only murine receptor mediating HDL-CE selective uptake, whereas a SR-BI-independent pathway specific to LDL can rescue SR-BI deficiency. The analysis of LDL recovered 3 h after injection in mice from different genotypes revealed that LDLs are significantly depleted in CE (reduction from 19% to 50% of the CE/protein ratios). A smaller LDL size in comparison with that of noninjected LDL was also detectable but was more evident for LDL recovered from normal mice. All LDL preparations migrate faster than noninjected LDL on agarose-barbital gels. Thus, both SR-BI-dependent and -independent pathways lead to substantial changes in LDL. Numerous epidemiological studies have demonstrated that the risk of developing coronary artery diseases is directly related to plasma concentrations of LDL cholesterol (1) and inversely associated with plasma levels of HDL (2). Plasma levels of LDL cholesterol are in large part regulated via the LDL receptor (LDLr), which mediates the clearance of LDL through a well-defined process involving endocytosis and degradation of the entire LDL particle (3, 4). In contrast, clearance of HDL cholesterol seems to be accomplished by another pathway called selective uptake, which involves the extraction of cholesteryl esters (CEs) from lipoproteins without concomitant degradation of its apolipoproteins (5). Although selective uptake is usually associated with HDL cholesterol, evidence suggests that this pathway may also act on other lipoproteins, such as LDL (6-9).The scavenger receptor class B type I (SR-BI) is a cell surface receptor that was initially found as a receptor for modified LDL (oxidized or acetylated) and maleylated BSA and was later shown to bind native lipoproteins (5, 10, 11). Although SR-BI can bind LDL with high affinity, attention has mainly been devoted to the relation between SR-BI and HDL, and SR-BI was demonstrated to mediate the selective uptake of HDL-CE in transfected cells (5,12,13). The abundance of SR-BI in steroidogenic organs and liver, the principal sites of cholesteryl ester selective uptake in vivo, has also been cited as an indication of SR-BI involvement in HDL metabolism (5, 14). However, the most convincing evidence for a role of SR-BI in HDL metabolism has come from studies using genetically manipulated mice. These studies demonstrated that a disruption of the SR-BI gene generates an increase in total plasma cholesterol levels, which is mainly associated with the appearance of large HDLs ...

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