Dietary Cholesterol Plays a Role in CD36-Mediated Atherogenesis in LDLR-Knockout Mice

Abstract

Objective— CD36 has been shown to play a role in atherosclerosis in the apolipoprotein E-knockout ( apoE ^o ) mouse. We observed no difference in aortic lesion area between Western diet (WD)-fed LDLR ^o and LDLR ^o / CD36 ^o mice. The objective was to understand the mechanism of CD36-dependent atherogenesis. Methods and Results— A poE ^o mice transplanted with bone marrow from LDLR ^o / CD36 ^o mice had significantly less aortic lesion compared with those transplanted with LDLR ^o marrow. Reciprocal macrophage transfer into hyperlipidemic apoE ^o and LDLR ^o animals showed that foam cell formation induced by in vivo modified lipoproteins was dependent on the lipoprotein, not macrophage type. LDLR ^o and LDLR ^o / CD36 ^o mice were fed a cholesterol-enriched diet (HC), and we observed significant lesion inhibition in LDLR ^o / CD36 ^o mice. LDL/plasma isolated from HC-fed LDLR ^o mice induced significantly greater jnk phosphorylation, cytokine release, and reactive oxygen species secretion than LDL/plasma from WD-fed LDLR ^o mice, and this was CD36-dependent. HC-fed LDLR ^o mice had higher circulating levels of cytokines than WD-fed mice. Conclusions— These data support the hypothesis that CD36-dependent atherogenesis is contingent on a proinflammatory milieu that promotes the creation of specific CD36 ligands, not solely hypercholesterolemia, and may explain the greater degree/accelerated rate of atherosclerosis observed in syndromes associated with inflammatory risk.