Abstract 151: Macrophage Specific Ablation Of Bmal1 Regulate Cholesterol Metabolism And Atherosclerosis

Abstract

Macrophages play a critical role in atherosclerosis. We have previously shown that Clock mutant and global or liver-specific Bmal1 deficient mice show enhanced atherosclerosis. Yet, the role of macrophage Bmal1 in cholesterol transport and atherosclerosis remains unknown. Here, we used global and macrophage-specific ablation of Bmal1 to clarify the role of Bmal1 in macrophage function in atherosclerosis. We found that macrophage-specific Bmal1 deficient mice show increased atherosclerosis. Biochemical studies showed that Bmal1 deficient macrophages exhibit increased expression of Lox-1 and Cd36 and take up more oxLDL. Furthermore, they show decreased expression of Abca1 and Abcg1 and reduced cholesterol efflux as well as in vivo reverse cholesterol transport. Thus, Bmal1 regulates macrophage cholesterol metabolism by regulating uptake of oxidized lipoproteins and cholesterol efflux pathways. Molecular studies showed that Bmal1 indirectly regulates Cd36 and Abca1/Abcg1 by modulating Nr1d1 and Znf202, respectively. We provide evidence that Bmal1 collaborates with Clock and interacts with Nr1d1 promoter. Furthermore, our studies show that Bmal1 interacts with both Clock and Npas2 to regulate Znf202. Thus, Bmal1 regulates two different transcription factors to regulate uptake of oxidized lipoproteins and cholesterol efflux. In summary, our data show that Bmal1 is a key regulator of cholesterol metabolism in macrophages and atherosclerosis. It regulates macrophage function by modulating the expression of different transcription factors. It is likely that augmentation of Bmal1 may prevent atherosclerosis.