Thursday, December 26, 2024
12/26/2024
Multiple biochemical, physiological, and behavioral processes are at least partially governed by circadian rhythms. We have shown that global deficiencies in Clock and Bmal1 increase atherosclerosis. In the past few years, two studies have published conflicting reports regarding the role of myeloid/macrophage (Mφ) Bmal1 in atherosclerosis. Therefore, we performed in-depth analyses and observed that Mφ-specific Bmal1 deficiency increases atherosclerosis in five different mouse models. Our mechanistic studies revealed that Mφ Bmal1 regulates three pathways in cholesterol metabolism. First, Bmal1 regulates uptake of modified lipoproteins by regulating Cd36 expression. Second, Bmal1 deficiency decreases cholesterol efflux by reducing the expression of ATP binding cassette subfamily G member 1 (Abcg1). Furthermore, Bmal1 partners with Npas2 to coordinately regulate Abcg1 via the Zinc finger protein 202 (Znf202) repressor. Third, Bmal1 deficiency impairs cholesterol egress from lysosomes due to dysregulation of NPC intracellular cholesterol transporter 1 (Npc1) and Npc2 in Bmal1 deficient Mφs. Based on these findings, we propose three aims to delineate comprehensively the role of Bmal1 in Mφ cholesterol metabolism. Aim 1: Circadian regulation of modified lipoprotein uptake. At the molecular level, we will test the hypothesis that Bmal1 regulates Cd36 by regulating Nuclear Receptor Subfamily 1 Group D Member 1 (Rev-erbα). For physiologic context, we will extend these studies to Mφ-specific Rev-erbα deficient mice. Aim 2: Molecular mechanisms controlling cholesterol efflux. We will test the hypothesis that Bmal1 deficiency increases Znf202 expression and that Bmal1:Npas2 heterodimers regulate Znf202. Higher Znf202 levels repress Abcg1 expression through binding to the GnT-box. Aim 3: Regulation of lysosomal cholesterol egress. We will test the hypothesis that Bmal1 interacts with the E-boxes in the promoters of Npc1 and Npc2 to regulate their circadian expression and lysosomal cholesterol egress. These studies are expected to elucidate key biochemical and molecular mechanisms regulated by Bmal1 that control modified lipoprotein uptake, cholesterol efflux from Mφs and cholesterol egress from lysosomes, thus providing comprehensive information regarding Mφ cholesterol homeostasis. These studies should additionally demonstrate that cholesterol metabolism and circadian regulatory mechanisms are intertwined, and that the deregulation of circadian pathways alters Mφ cholesterol homeostasis, thereby enhancing the risk of atherosclerosis. The proposed studies are expected to substantially advance fundamental knowledge in two fields of biology—chronobiology and cholesterol metabolism.
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