Scavenger Receptors Class A-I/II and CD36 Are the Principal Receptors Responsible for the Uptake of Modified Low Density Lipoprotein Leading to Lipid Loading in Macrophages

TLDR

Modified LDL is avidly taken up by macrophages through scavenger receptors, with SR‑A and CD36 shown to mediate most of this uptake while the role of other SRs remains unclear. The study aimed to determine the combined effect of deleting SR‑A and CD36 on macrophage lipid uptake and to evaluate whether other SRs compensate. Researchers generated mice lacking both SR‑A and CD36 and measured macrophage lipid uptake and accumulation of modified LDL. SR‑A and CD36 account for 75–90 % of modified LDL degradation, and their absence prevents cholesterol ester accumulation in macrophages, indicating other SRs do not compensate.

Abstract

Modification of low density lipoprotein (LDL) can result in the avid uptake of these lipoproteins via a family of macrophage transmembrane proteins referred to as scavenger receptors (SRs). The genetic inactivation of either of two SR family members, SR-A or CD36, has been shown previously to reduce oxidized LDL uptake<i>in vitro</i> and atherosclerotic lesions in mice. Several other SRs are reported to bind modified LDL, but their contribution to macrophage lipid accumulation is uncertain. We generated mice lacking both SR-A and CD36 to determine their combined impact on macrophage lipid uptake and to assess the contribution of other SRs to this process. We show that SR-A and CD36 account for 75–90% of degradation of LDL modified by acetylation or oxidation. Cholesteryl ester derived from modified lipoproteins fails to accumulate in macrophages taken from the double null mice, as assessed by histochemistry and gas chromatography-mass spectrometry. These results demonstrate that SR-A and CD36 are responsible for the preponderance of modified LDL uptake in macrophages and that other scavenger receptors do not compensate for their absence.