NATIVE AND MODIFIED LOW-DENSITY LIPOPROTEINS INCREASE THE FUNCTIONAL EXPRESSION OF THE MACROPHAGE CLASS-B SCAVENGER RECEPTOR, CD36

The uptake of oxidized low density lipoprotein (OxLDL) by macrophages is a key event implicated in the initiation and development of atheros clerotic lesions, Two macrophage surface receptors, CD36 (a class B sc avenger receptor) and the macrophage scavenger receptor (a class A sca venger receptor), have been identified as the major receptors that bin d and internalize OxLDL. Expression of CD36 in monocyte/macrophages in tissue culture is dependent both on the differentiation state as well as exposure to soluble mediators (cytokines and growth factors), The regulatory mechanisms of this receptor in vivo are undetermined as is the role of lipoproteins themselves in modulating CD36 expression. We studied the effect of lipoproteins, native LDL and modified LDL (acety lated LDL (AcLDL) and OxLDL) on the expression of CD36 in J774 cells, a murine macrophage cell line, Exposure to lipoproteins resulted in a marked induction of CD36 mRNA expression (4-8-fold), Time course studi es showed that maximum induction was observed 2 h after treatment with AcLDL and at 4 h with LDL and OxLDL, Increased expression of CD36 mRN A persisted for 24 h with each treatment group, Induction of CD36: mRN A expression was paralleled by an increase in CD36 protein as determin ed by Western blot with the greatest induction by OxLDL (4-fold), In t he presence of actinomycin D, treatment of macrophages with LDL, AcLDL , or OxLDL did not affect. CD36 mRNA stability, implying that CD36 mRN A was transcriptionally regulated by lipoproteins. To determine the me chanism(s) by which lipoproteins increased expression of CD36 we evalu ated the effects of lipoprotein components on CD36 mRNA. expression, A poB 100 increased CD36 mRNA expression significantly, whereas phosphol ipid/cholesterol liposomes had. less effect, Incubation of macrophages with bovine serum albumin or HDL reduced expression of CD36 mRNA in a dose-dependent manner. Finally, to evaluate the in vivo relevance of the induction of CD36 mRNA expression by lipoproteins, peritoneal macr ophages were isolated from mice following intraperitoneal injection of lipoproteins. Macrophage expression of CD36 mRNA was significantly in creased by LDL, AcLDL, or OxLDL in relation to mice infused with phosp hate-buffered saline, with OxLDL causing the greatest induction (8-fol d). This is the first demonstration that exposure to free and esterifi ed lipids augments functional expression of the class B scavenger rece ptor, CD36, These data imply that lipoproteins can further contribute to foam cell development in atherosclerosis by up-regulating a major O xLDL receptor.